Glucosylceramide synthase inhibitors for the treatment of diseases

ABSTRACT

Described herein are compounds of Formula I, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds to treat or prevent diseases or conditions associated with the enzyme glucosylceramide synthase (GCS).

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of priority of U.S.Provisional Application No. 62/131,703, filed Mar. 11, 2015, the contentof which is hereby incorporated by reference in its entirety.

FIELD

Described herein are compounds, methods of making such compounds,pharmaceutical compositions and medicaments containing such compounds,and methods of using such compounds to treat or prevent diseases orconditions associated with the enzyme glucosylceramide synthase (GCS).

BACKGROUND

Glucosylceramide synthase (GCS) is a key enzyme which catalyzes theinitial glycosylation step in the biosynthesis of glucosylceramide-basedglycosphingolipids (GSLs) namely via the transfer of glucose fromUDP-glucose (UDP-Glc) to ceramide to form glucosylceramide. GCS is atransmembrane, type III integral protein localized in the cis/medialgolgi. Glycosphingolipids (GSLs) are believed to be integral in manycell membrane events, including cellular interactions, signaling, andtrafficking. Synthesis of GSL structures has been shown (Proc. Natl.Acad. Sci CJSA 1999, 96(16), 9142-9147) to be essential for embryonicdevelopment and for the differentiation of some tissues. Ceramide playsa central role in sphingolipid metabolism, and downregulation of GCSactivity has been shown to have marked effects on the sphingolipidpattern with diminished expression of glycosphingolipids. Sphingolipidshave a role in physiological as well as pathological cardiovascularconditions. In particular, sphingolipids and their regulating enzymesappear to play a role in adaptive responses to chronic hypoxia in theneonatal rat heart (Prostaglandins & Other Lipid Mediators 2005,78(1-4), 249-263).

GCS inhibitors have been proposed for the treatment of a variety ofdiseases (see, for example, WO2005068426). Such diseases includeglycolipid storage diseases (e.g., Tay Sachs, Sandhoffs, GM1gangliosidosis, Niemanns-Pick, and Fabry diseases), diseases associatedwith glycolipid accumulation (e.g., Gaucher disease), diseases thatcause renal hypertrophy or hyperplasia such as diabetic nephropathy,diseases that cause hyperglycemia or hyperinsulinemia, cancers in whichglycolipid synthesis is abnormal, infectious diseases caused byorganisms which use cell surface glycolipids as receptors, infectiousdiseases in which synthesis of glucosylceramide is essential orimportant, diseases in which excessive glycolipid synthesis occurs(e.g., atherosclerosis, polycystic kidney disease, and renalhypertrophy), neuronal disorders, neuronal injury, inflammatory diseasesor disorders associated with macrophage recruitment and activation(e.g., rheumatoid arthritis, Crohn's disease, asthma and sepsis), pain(see WO2008011483—neuropathic pain, inflammatory pain, headache pain,somatic pain, visceral pain, referred pain), cognitive disorders (seeWO2008/109286—agnosia; amnesia; aphasia; an apraxia; delirium; dementiaincluding AIDS dementia complex, Binswanger's disease, dementia withLewy Bodies, frontotemporal dementia, mild cognitive impairment,multi-infarct dementia, Pick's disease, semantic dementia, seniledementia, and vascular dementia; and learning disorders includingAsperger's syndrome, attention deficit disorder, attention deficithyperactivity disorder, autism, childhood disintegrative disorder, andRett syndrome), neurodegenerative disorders (such as Alzheimer'sdisease, corticobasal degeneration, Creutzfeldt-Jacob disease,frontotemporal lobar degeneration, Huntington disease, multiplesclerosis, normal pressure hydrocephalus, organic chronic brainsyndrome, Parkinson's disease, Pick disease, progressive supranuclearpalsy, and senile dementia (Alzheimer type), glomerular disease, anddiabetes mellitus and obesity (see WO 2006053043)). Renal hypertrophyinduced by diabetes is associated with enhanced synthesis ofglycosphingolipids such as glucosylceramide and ganglioside GM₃, whichaccumulate in the kidney of rats (J. Clin. Invest. 1993, 91(3), 797).

It has been shown that overexpression of GCS is implicated in multi-drugresistance and disrupts ceramide-induced apoptosis. For example,Turzanski et al. (Experimental Hematology 2005, 33(1), 62-72) have shownthat ceramide induces apoptosis in acute myeloid leukemia (AML) cellsand that P-glycoprotein (p-gp) confers resistance to ceramide-inducedapoptosis, with modulation of the ceramide-glucosylceramide pathwaymaking a marked contribution to this resistance in TF-I cells. Thus, GCSinhibitors can be useful for treatment of proliferative disorders (suchas cancer) by inducing apoptosis in diseased cells.

Sandhoff (or type 2 GM2 gangliosidosis) is caused by a deficiency inβ-hexosaminidase A and B activity which leads to an accumulation of theganglioside GM₂ and other glycolipids causing damage to the centralnervous system and eventually is lethal (PLoS One 2011, 6(6), e21758).Tay-Sachs disease (or GM₂ gangliosidosis) is caused by a deficiency inβ-hexosaminidase A which lead to an accumulation of gangliosides in thebrain's nerve cells eventually leading to their premature death.Intravenous injection of the missing enzyme(s) is not a viable option asof the enzymes does cross the blood-brain barrier (Genetics in Medicine2009, 1(6), 425). Glucosylceramide synthase is a key enzyme in thesynthesis of glucosylceramide and other glycosphingolipids. Itsinhibition can decrease the amount of the glycosphingolipids whichaccumulate in Sandhoff disease.

Fabry disease is caused by loss of activity of the lysosomal hydrolaseα-galactosidase which leads to an accumulation of glycosphingolipids(particularly globotriaosylceramide) causing pain, renal disease andfailure, cerebral vascular disease, and myocardial infarction (KidneyInternational 2000, 57, 446). One treatment strategy is to provide thedefective enzyme to the patient; however, enzyme replacement therapy canonly slow the progression of the disease and is not a cure. Analternative or complementary strategy is one where glucosylceramidesynthase, a key enzyme in the synthesis of glycosphingolipids, isinhibited with a small molecule thus decreasing the amount ofglobotriaosylceramide and other glucosylceramide-based lipids that needto be broken down by hydrolase α-galactosidase.

Gaucher disease is caused by a defect in the enzyme lysosomalglucocerebrosidase which is responsible for catalyzing the breakdown ofglucosylceramide which then accumulates in tissues of affected people(J. Org. Chem. 2007, 72(4), 1088) causing liver malfunction, skeletaldisorders, painful bone lesions, hypersplenism, pancytopenia, andneurological symptoms (convulsions, hypertonia, mental retardation,apnea, dementia, and ocular muscle apraxia). One treatment strategy isto provide the defective enzyme to the patient; however, enzymereplacement therapy is not suitable for all patients and does notaddress the neurological manifestations of the disease for those withtype 2 and type 3. An alternative or complementary strategy is one whereglucosylceramide synthase is inhibited with small molecules thusdecreasing the amount of glucosylceramide that needs to be broken downby glucocerebrosidase.

Nonalcoholic fatty liver disease (NALD) is a disease where fataccumulates in the liver of people who drink little or no alcohol andresults in inflammation and scarring of the liver which can progress toliver failure. Inhibition of glucosylceramide synthase in ob/ob micelowered glucose levels, lowered liver/body weight ratio, decreased theaccumulation of triglycerides, and prevented and reversed steatosis(Hepatology 2009, 50(1), 85-93). Thus GCS inhibitors are useful for theprevention and treatment of NALD.

Polycystic kidney disease (PKD) is a genetic disease characterized bynoncancerous cysts which are filled with fluid and cause the kidneys toenlarge which can result in a decrease in quality of life (e.g.,headaches, high blood pressure, back and side pain, colon problems,mitral valve prolapsed, and kidney stones) and can be life-threatening(e.g., kidney failure, aneurysm in the brain, and high blood pressurewhich can lead to heart disease and stroke). PKD can also damage theliver, spleen, pancreas, vasculature, testes, seminal vesicles, andintestines. Glucosylceramide and ganglioside GM₃ levels in the kidneyare higher than in normal tissue (Nat Med 2010, 16(7), 788). Thus,blocking the synthesis of glucosylceramide with an inhibitor of GCS canbe useful in the treatment of PKD to reduce new cyst formation (partialor complete inhibition of cystogenesis), reduce cyst mass, reduce thesize and number of cysts, and/or reduce the severity of the symptomsassociated. All current treatments for PKD address symptoms and do nottreat the underlying cause of the disease (Nat Med 2010, 16(7), 788).

SUMMARY

In one aspect, provided is a compound of Formula I:

-   where:-   R¹ is H; or R¹ and R² together form —OCH₂CH₂O—;-   R² is C₃₋₆ cycloalkyloxy or 3-6 membered heterocycloalkyloxy;-   R³ is H or halogen;-   R⁴ is H or C₁₋₄ alkyl;-   R⁵ and R^(5A) are each independently H or C₁₋₄ alkyl;-   X is N or O, and when X is N, the dashed line is a bond to form a    double bond, and when X is O, the dashed line is not a bond to form    a single bond;-   Y is C(R⁶)₂, or O; with the proviso that X and Y are not both O;-   R⁶ at each occurrence is independently H or C₁₋₄ alkyl;-   Ring A is phenylene, naphthylene, or 5-10 membered heteroarylene;-   R⁷ at each occurrence is independently halogen, C₁₋₆ alkyl, C₁₋₆    alkoxy, C₃₋₆ cycloalkyloxy, (C₃₋₆ cycloalkyl)C₁₋₆ alkoxy, phenyl, or    5-6 membered heteroaryl, wherein the phenyl and heteroaryl are each    optionally substituted with 1, 2, or 3 R⁸;-   p is 0, 1, or 2;-   R⁸ at each occurrence is independently halogen, cyano, amino, C₁₋₆    alkylamino, C₁₋₆ dialkylamino, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆    haloalkoxy, aminocarbonyl, C₁₋₆ alkylaminocarbonyl, or C₁₋₆    dialkylaminocarbonyl;-   Ring B is a 4-6 membered heterocycloalkyl ring;-   R⁹ at each occurrence is independently halogen, OR¹⁰, or N(R¹⁰)₂;-   R¹⁰ at each occurrence is independently H or C₁₋₄ alkyl;-   q is 0, 1, 2, 3, or 4; and-   optionally a single stereoisomer or mixture of stereoisomers thereof    and-   additionally optionally a pharmaceutically acceptable salt thereof.

In a further aspect, provided is a pharmaceutical compositioncomprising:

1) a Compound of Formula I optionally as a single stereoisomer ormixture of stereoisomers thereof and additionally optionally as apharmaceutically acceptable salt thereof, and2) a pharmaceutically acceptable excipient.

In a further aspect, provided is a method of treating a disease ordisorder comprising administering a Compound of Formula I, optionally asa single stereoisomer or mixture of stereoisomers thereof andadditionally optionally as a pharmaceutically acceptable salt thereof,or the pharmaceutical composition thereof additionally comprising apharmaceutically acceptable excipient.

DETAILED DESCRIPTION Abbreviations

Abbreviation Meaning aq aqueous Boc tert-butoxycarbonyl CBzcarbobenzyloxy conc concentrated DCM dichlorormethane DIPEAdiisoproylethylamine DMF dimethylformamide DMP Dess-Martin periodinaneDMSO dimethyl sulfoxide EDCI1-ethyl-3-(3-dimethylaminopropyl)carbodiimide h hours HATUO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate HOBt hydroxybenzotriazole LC-MS liquidchromatography-mass spectrometry LDA lithium diisopropyl amide mgmilligram mHz megahertz mL milliliter μL microliter Ms mesyl NBSN-bromosuccinimide NMP N-methyl pyrrolidone NMR nuclear magneticresonance rt or RT room temperature sat saturated TBDMStert-butyldimethylsilyl TFA trifluoroacetic acid THF tetrahydrofuran TLCthin layer chromatography

Definitions

To facilitate understanding of the disclosure set forth herein, a numberof terms are defined below. Generally, the nomenclature used herein andthe laboratory procedures in organic chemistry, medicinal chemistry, andpharmacology described herein are those well-known and commonly employedin the art. Unless defined otherwise, all technical and scientific termsused herein generally have the same meaning as commonly understood byone of ordinary skill in the art to which this disclosure belongs.

As used throughout this application and the appended claims, thefollowing terms have the following meanings:

“About” preceding a numerical value refers to a range of values ±10% ofthe value specified.

“Acceptable” with respect to a formulation, composition or ingredient,as used herein, means having no persistent detrimental effect on thegeneral health of the subject being treated.

“Alkoxy” means an —OR group where R is alkyl, as defined herein.Illustrative examples include, but are not limited to, methoxy, ethoxy,propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

“Alkyl” means a straight or branched saturated hydrocarbon radicalcontaining from 1-10 carbon atoms, in another example 1-6 carbon atoms.Illustrative examples include, but are not limited to, methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl,isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl,2,3-dimethylhexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

“Alkylamino” means a —NHR radical where R is alkyl as defined herein,e.g., methylamino, ethylamino, n-, iso-propylamino, n-, iso-,tert-butylamino, and the like.

“Alkylaminocarbonyl” means a —C(O)R group where R is alkylamino, asdefined herein.

“Amino” means an —NH₂ group.

“Aminocarbonyl” means a —C(O)R group where R is amino, as definedherein.

“Aryl” means a monovalent six- to fourteen-membered, mono- orbi-carbocyclic ring, wherein the monocyclic ring is aromatic and atleast one of the rings in the bicyclic ring is aromatic. Representativeexamples include phenyl, naphthyl, and indanyl, and the like.

“Phenylene” means a divalent radical formed by removal of a hydrogenatom from phenyl.

“Naphthylene” means a divalent radical formed by removal of a hydrogenatom from naphthyl.

“Indanylene” means a divalent radical formed by removal of a hydrogenatom from indanyl.

“Cycloalkyl” means a monocyclic or fused bicyclic, saturated orpartially unsaturated (but not aromatic), hydrocarbon radical of threeto ten carbon ring atoms. Fused bicyclic hydrocarbon radical includesbridged rings. Cycloalkyl includes spirocycloalkyl rings. Unless statedotherwise, the valency of the group may be located on any atom of anyring within the radical, valency rules permitting. One or two ringcarbon atoms may be replaced by a —C(O)—, —C(S)—, or —C(═NH)— group.

In certain embodiments, cycloalkyl groups include but are not limitedto:

“Cycloalkyloxy” means an —OR group where R is cycloalkyl, as definedherein.

“(Cycloalkyl)alkoxy” means an —OR group where R is alkyl, as definedherein, where the R is substituted by a cycloalkyl group, as definedherein. Illustrative examples include, but are not limited to,cyclohexylmethoxy, cyclohexylethoxy, cyclohexylpropoxy,cyclohexyl-2-propoxy, cyclohexylbutoxy, cyclohexyltert-butoxy,cyclohexylpentyloxy, cyclohexyihexyloxy, cyclopentylmethoxy,cyclopentylethoxy, cyclopentylpropoxy, cyclopentyl-2-propoxy,cyclopentylbutoxy, cyclopentyltert-butoxy, cyclopentylpentyloxy, andcyclopentylhexyloxy.

“Dialkylamino” means an —NRR′ radical where R and R′ are independentlyalkyl as defined herein, e.g., dirnethylamino, diethylamino,N,N-methylpropylamino or N,N-methylethylamino, and the like.

“Dialkylaminocarbonyl” means a —C(O)R group where R is dialkylamino, asdefined herein.

“Halo” or “halogen” means a fluoro, chloro, bromo, or iodo group.

“Haloalkoxy” means an alkoxy group, as defined herein, substituted withone or more halo atoms. In certain embodiments, the alkoxy group issubstituted with 1, 2, 3, 4 or 5 halo atoms; or with 1, 2, or 3 haloatoms; or with one halo atom.

“Heteroaryl” means monocyclic, fused bicyclic, or fused tricyclic,radical of 5 to 14 ring atoms containing one or more, in another exampleone, two, three, or four ring heteroatoms independently selected from—O—, —S(O)_(n)— (n is 0, 1, or 2), —N—, —N(H)—, and N-oxide, and theremaining ring atoms being carbon, wherein the ring comprising amonocyclic radical is aromatic and wherein at least one of the fusedrings comprising a bicyclic or tricyclic radical is aromatic (but doesnot have to be a ring which contains a heteroatom, e.g.2,3-dihydrobenzo[b][1,4]dioxin-6-yl). One or two ring carbon atoms ofany nonaromatic rings comprising a bicyclic or tricyclic radical may bereplaced by a —C(O)—, —C(S)—, or —C(═NH)— group. Fused bicyclic radicalincludes bridged ring systems. Unless stated otherwise, the valency maybe located on any atom of any ring of the heteroaryl group, valencyrules permitting.

“Heteroarylene” means a divalent radical formed by removal of a hydrogenatom from heteroaryl, as defined herein.

In certain embodiments, heteroaryl includes, but is not limited to,triazolyl, tetrazolyl, pyrrolyl, imidazolyl, thienyl, furanyl,pyrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiadiazolyl, indolyl,2,3-dihydro-1H-indolyl (including, for example,2,3-dihydro-1H-indol-2-yl or 2,3-dihydro-1H-indol-5-yl, and the like),indazolyl, phthalimidyl, benzimidazolyl, benzoxazolyl, benzofuranyl,benzothienyl, benzopyranyl, benzothiazolyl, pyridinyl, pyrazinyl,pyrimidinyl, pyridazinyl, quinolinyl, isoquinolinyl,tetrahydroisoquinolinyl (including, for example,tetrahydroisoquinolin-4-yl or tetrahydroisoquinolin-6-yl, and the like),pyrrolo[3,2-c]pyridinyl (including, for example,pyrrolo[3,2-c]pyridin-2-yl or pyrrolo[3,2-c]pyridin-7-yl, and the like),pyrrolo[1,2-b]pyridazinyl, imidazo[1,2-a]pyridinyl, thiazolyl,benzo[d][1,3]dioxolyl, 2,3-dihydrobenzo[b][1,4]dioxinyl,furo[2,3-d]thiazolyl, thieno[2,3-d]oxazolyl, thieno[3,2-b]furanyl,furo[2,3-d]pyrimidinyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl,6,7-dihydro-5H-cyclopenta[b]pyridinyl, and7,8-dihydro-6H-cyclopenta[g]quinoxalinyl.

“Benzothiophenylene” means a divalent radical formed by removal of ahydrogen atom of benzothiophenyl.

“Indazolylene” means a divalent radical formed by removal of a hydrogenatom of indazolyl.

“Quinolylene” means a divalent radical formed by removal of a hydrogenatom of quinolylene.

“Heterocycloalkyl” means a saturated or partially unsaturated (but notaromatic) monovalent monocyclic group of 3 to 9 ring atoms or asaturated or partially unsaturated (but not aromatic) monovalent fusedbicyclic group of 5 to 12 ring atoms in which one or more heteroatoms,for example one, two, three, or four ring heteroatoms, independentlyselected from —O—, —S(O)_(n)— (n is 0, 1, or 2), —N═, —NH—, and N-oxide,the remaining ring atoms being carbon. One or two ring carbon atoms maybe replaced by a —C(O)—, —C(S)—, or —C(═NH)— group. Fused bicyclicradical includes bridged ring systems. Unless otherwise stated, thevalency of the group may be located on any atom of any ring within theradical, valency rules permitting.

In certain embodiments, heterocycloalkyl includes, but is not limitedto, azetidinyl, pyrrolidinyl, 2-oxopyrrolidinyl,2,5-dihydro-1H-pyrrolinyl, 2,5-dioxo-1H-pyrrolyl,2,5-dioxo-pyrrolidinyl, 2,5-dihydro-1H-pyrrolyl, piperidinyl,2-oxopiperidinyl, 4-piperidonyl, morpholinyl, piperazinyl,2-oxopiperazinyl, dioxopiperazinyl, pyranyl, tetrahydropyranyl,tetrahydrothiopyranyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl,1,4-dioxanyl, thiomorpholinyl, thiamorpholinyl, perhydroazepinyl,pyrazolidinyl, imidazolinyl, imidazolidinyl, 2,4-dioxo-imidazolidinyl,dihydropyridinyl, tetrahydropyridinyl, oxazolinyl, oxazolidinyl,isoxazolidinyl, thiazolinyl, thiazolidinyl, quinuclidinyl,isothiazolidinyl, octahydroindolyl, octahydroisoindolyl,decahydroisoquinolyl, tetrahydrofuryl, 2-azaspiro[3.3]heptanyl,7-azabicyclo[2.2.1]heptanyl, and 8-azabicyclo[3.2.1]octanyl, and N-oxide(for example 1-oxido-pyrrolidin-1-yl) thereof.

“Heterocycloalkyloxy” means an —OR group where R is heterocycloalkyl, asdefined herein.

“Stereoisomers” include (but are not limited to) geometric isomers,enantiomers, diastereomers, and mixtures of geometric isomers,enantiomers or diastereomers. In some embodiments, individualstereoisomers of compounds are prepared synthetically from commerciallyavailable starting materials which contain asymmetric or chiral centersor by preparation of racemic mixtures followed by resolution. Thesemethods of resolution are exemplified by (1) attachment of a mixture ofenantiomers to a chiral auxiliary, separation of the resulting mixtureof diastereomers by recrystallization or chromatography and liberationof the optically pure product from the auxiliary or (2) directseparation of the mixture of optical enantiomers on chiralchromatographic column.

As used herein, “amelioration” of the symptoms of a particular disorderby administration of a particular compound or pharmaceutical compositionrefers to any lessening of severity, delay in onset, slowing ofprogression, or shortening of duration, whether permanent or temporary,lasting or transient that can be attributed to or associated withadministration of the compound or composition.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of an agent or a compoundbeing administered which will relieve to some extent one or more of thesymptoms of the disease or condition being treated. The result includesreduction and/or alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Forexample, an “effective amount” for therapeutic uses is the amount of thecomposition comprising a compound as disclosed herein required toprovide a clinically significant decrease in disease symptoms. Anappropriate “effective” amount in any individual case is determinedusing any suitable technique, such as a dose escalation study.

“Excipient” or “pharmaceutically acceptable excipient” means apharmaceutically-acceptable material, composition, or vehicle, such as aliquid or solid filler, diluent, solvent, or encapsulating material. Inone embodiment, each component is “pharmaceutically acceptable” in thesense of being compatible with the other ingredients of a pharmaceuticalformulation, and suitable for use in contact with the tissue or organ ofhumans and animals without excessive toxicity, irritation, allergicresponse, immunogenicity, or other problems or complications,commensurate with a reasonable benefit/risk ratio. See, e.g., Remington:The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams &Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients,6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the AmericanPharmaceutical Association: 2009; Handbook of Pharmaceutical Additives,3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007;Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRCPress LLC: Boca Raton, Fla., 2009.

“Pharmaceutically acceptable salt” refers to a formulation of a compoundthat does not cause significant irritation to an organism to which it isadministered and does not abrogate the biological activity andproperties of the compound. In certain instances, pharmaceuticallyacceptable salts are obtained by reacting a compound described herein,with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid,nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid and the like. In some instances,pharmaceutically acceptable salts are obtained by reacting a compoundhaving acidic group described herein with a base to form a salt such asan ammonium salt, an alkali metal salt, such as a sodium or a potassiumsalt, an alkaline earth metal salt, such as a calcium or a magnesiumsalt, a salt of organic bases such as dicyclohexylamine,N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts withamino acids such as arginine, lysine, and the like, or by other methodspreviously determined. The pharmacologically acceptable salt are notspecifically limited as far as it can be used in medicaments. Examplesof a salt that the compounds described herein forms with a base includethe following: salts thereof with inorganic bases such as sodium,potassium, magnesium, calcium, and aluminum; salts thereof with organicbases such as methylamine, ethylamine and ethanolamine; salts thereofwith basic amino acids such as lysine and ornithine; and ammonium salt.The salts may be acid addition salts, which are specifically exemplifiedby acid addition salts with the following: mineral acids such ashydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,nitric acid, and phosphoric acid: organic acids such as formic acid,acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid,fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid,citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic aminoacids such as aspartic acid and glutamic acid.

The term “pharmaceutical composition” refers to a mixture of a compounddescribed herein with other chemical components, such as carriers,stabilizers, diluents, dispersing agents, suspending agents, thickeningagents, and/or excipients. The pharmaceutical composition facilitatesadministration of the compound to an organism. Multiple techniques ofadministering a compound exist in the art including, but not limited to:intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary andtopical administration.

“Subject” refers to a mammal, but not limited to, a human, primate,monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.The terms “subject” and “patient” are used interchangeably herein inreference, for example, to a mammalian subject, such as a human. Incertain embodiments, the subject is a human.

“Treat,” “treating,” and “treatment,” in the context of treating adisease or disorder, are meant to include alleviating or abrogating adisorder, disease, or condition, or one or more of the symptomsassociated with the disorder, disease, or condition; or to slowing theprogression, spread or worsening of a disease, disorder or condition orof one or more symptoms thereof. Often, the beneficial effects that asubject derives from a therapeutic agent do not result in a completecure of the disease, disorder or condition.

EMBODIMENTS

The following paragraphs present a number of embodiments of thecompounds disclosed herein, where the appropriate substituents areindependently selected as set forth in in the Summary and hereafter.Thus, provided are compounds of the recited formulae as defined by anycombination of the broader and narrower definitions of thesesubstituents as set forth herein. In each instance the embodimentincludes both the recited compound(s) as well as a single stereoisomeror mixture of stereoisomers thereof, as well as a pharmaceuticallyacceptable salt thereof.

The compounds described herein, as well as their correspondingpharmaceutically acceptable salts thereof, can exist inisotopically-labeled form, in which one or more atoms of the compoundsare replaced by an atom having the same atomic number but an atomic massdifferent from the atomic mass usually found in nature. Examples ofisotopes that can be incorporated into compounds described hereininclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,sulfur, fluorine, and chloride, such as ²H (deuterium), ³H (tritium),¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.Isotopically labeled compounds described herein, as well aspharmaceutically acceptable salts thereof, generally can be prepared bycarrying out the procedures disclosed in the Schemes and/or in theExamples and Preparations herein, by substituting a readily availableisotopically labeled reagent for a non-isotopically labeled reagent.

In one aspect, provided is a compound of Formula I:

wherein

-   R¹ is H; or R¹ and R² together form —OCH₂CH₂O—;-   R² is C₃₋₆ cycloalkyloxy or 3-6 membered heterocycloalkyloxy;-   R³ is H or halogen;-   R⁴ is H or C₁₋₄ alkyl;-   R⁵ and R^(5A) are each independently H or C₁₋₄ alkyl;-   X is N or O, and when X is N, the dashed line is a bond to form a    double bond, and when X is O, the dashed line is not a bond to form    a single bond;-   Y is C(R⁶)₂, or O; with the proviso that X and Y are not both O;-   R⁶ at each occurrence is independently H or C₁₋₄ alkyl;-   Ring A is phenylene, naphthylene, or 5-10 membered heteroarylene;-   R⁷ at each occurrence is independently halogen, C₁₋₆ alkyl, C₁₋₆    alkoxy, C₃₋₆ cycloalkyloxy, (C₃₋₆ cycloalkyl)C₁₋₆ alkoxy, phenyl, or    5-6 membered heteroaryl, wherein the phenyl and heteroaryl are each    optionally substituted with 1, 2, or 3 R⁸;-   p is 0, 1, or 2;-   R⁸ at each occurrence is independently halogen, cyano, amino, C₁₋₆    alkylamino, C₁₋₆ dialkylamino, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆    haloalkoxy, aminocarbonyl, C₁₋₆ alkylaminocarbonyl, or C₁₋₆    dialkylaminocarbonyl;-   Ring B is a 4-6 membered heterocycloalkyl ring;-   R⁹ at each occurrence is independently halogen, OR¹⁰, or N(R¹⁰)₂;-   R¹⁰ at each occurrence is independently H or C₁₋₄ alkyl;-   q is 0, 1, 2, 3, or 4; and-   optionally a single stereoisomer or mixture of stereoisomers    thereof, and-   additionally optionally a pharmaceutically acceptable salt thereof.

In another aspect, provided is a compound of Formula I:

wherein

-   R¹ is H; or R¹ and R² together form —OCH₂CH₂O—;-   R² is C₃₋₆ cycloalkyloxy or 3-6 membered heterocycloalkyloxy;-   R³ is H or halogen;-   R⁴ is H or C₁₋₄ alkyl;-   R⁵ and R^(5A) are each independently H or C₁₋₄ alkyl;-   X is N or O, and when X is N, the dashed line is a bond to form a    double bond, and when X is O, the dashed line is not a bond to form    a single bond;-   Y is C(R⁶)₂, or O; with the proviso that X and Y are not both O;-   R⁶ at each occurrence is independently H or C₁₋₄ alkyl;-   Ring A is phenylene, naphthylene, or 5-10 membered heteroarylene;-   R⁷ at each occurrence is independently halogen, C₁₋₆ alkyl, phenyl,    or 5-6 membered heteroaryl, wherein the phenyl and heteroaryl are    each optionally substituted with 1, 2, or 3 R⁸;-   p is 0, 1, or 2;-   R⁸ at each occurrence is independently halogen, cyano, amino, C₁₋₆    alkylamino, C₁₋₆ dialkylamino, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆    haloalkoxy, aminocarbonyl, C₁₋₆ alkylaminocarbonyl, or C₁₋₆    dialkylaminocarbonyl;-   Ring B is a 4-6 membered heterocycloalkyl ring;-   R⁹ at each occurrence is independently halogen, OR¹⁰, or N(R¹⁰)₂;-   R¹⁰ at each occurrence is independently H or C₁₋₄ alkyl;-   q is 0, 1, 2, 3, or 4; and-   optionally a single stereoisomer or mixture of stereoisomers    thereof, and-   additionally optionally a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I is that wherein

is selected from

wherein the asterix indicates the point of attachment to the rest of themolecule.

In some embodiments, the compound of Formula I is that wherein p is 0,1, or 2; or p is 0 or 1; or p is 1 or 2; or p is 0; or p is 1; or p is2.

In some embodiments, the compound of Formula I is that wherein q is 0,1, 2, 3 or 4; or q is 0, 1, 2 or 3; or q is, 1 or 2; or q is 0 or 1; orq is 0; or q is 1; or q is 2; or q is 3; or q is 4. In some embodiments,the compound of Formula I is that wherein q is 1, 2, 3 or 4; or q is 2,3 or 4; or q is 3 or 4; or q is 4. In some embodiments, the compound ofFormula I is that wherein q is 0, 1, or 2; or q is 0 or 1; or q is 1 or2; or q is 0; or q is 1; or q is 2.

In some embodiments, the compound of Formula I is that wherein Ring A isbicyclic; or Ring A is bicyclic with 1-3 nitrogen atoms; or Ring A isbicyclic with 1-2 nitrogen atoms. In some embodiments, Ring A isphenylene, naphthylene, benzothiophenylene, indazolylene, orquinolylene. In some embodiments, Ring A is phenylene and R⁷ is phenylor thienyl, each substituted with halogen. In some embodiments, R⁷ isphenyl substituted with halogen, or thienyl substituted with Cl. In someembodiments, R⁷ is phenyl substituted with halogen. In some embodiments,R⁷ is thienyl substituted with Cl.

In some embodiments, the compound of Formula I is that wherein Ring A isphenylene and R⁷ is C₁₋₆ alkoxy, C₃₋₆ cycloalkyloxy, or (C₃₋₆cycloalkyl)C₁₋₆ alkoxy. In some embodiments, Ring A is phenylene and R⁷is alkoxy. In some embodiments, Ring A is phenylene and R⁷ iscycloalkoxy. In some embodiments, Ring A is phenylene and R⁷ iscycloalkylalkoxy. In some embodiments, Ring A is phenylene and R⁷ iscyclohexylmethoxy.

In some embodiments, Ring A is phenylene, naphthylene, or 5-10 memberedheteroarylene; where the phenylene is substituted with phenyl, or 5-6membered heteroaryl, wherein the phenyl and heteroaryl are eachoptionally substituted with 1, 2, or 3 R⁸; and the naphthylene andheteroarylene are each independently substituted with 1 or 2 halogen orC₁₋₆ alkyl. In some embodiments, Ring A is phenylene substituted withphenyl or 5-6 membered heteroaryl, wherein the phenyl and heteroaryl areeach independently optionally substituted with 1, 2, or 3 R⁸. In someembodiments, Ring A is naphthylene or 5-10 membered heteroarylene, wherethe naphthylene and heteroarylene are each independently optionallysubstituted with 1 or 2 halogen, C₁₋₆ alkyl.

In some embodiments, Ring A is phenylene; where the phenylene issubstituted with C₁₋₆ alkoxy, C₃₋₆ cycloalkyloxy, (C₃₋₆ cycloalkyl)C₁₋₆alkoxy, phenyl, or 5-6 membered heteroaryl, wherein the phenyl andheteroaryl are each optionally optionally substituted with 1, 2, or 3R⁸. In some embodiments, Ring A is phenylene substituted with C₃₋₆cycloalkyloxy, (C₃₋₆ cycloalkyl)C₁₋₆ alkoxy, phenyl, or 5-6 memberedheteroaryl, wherein the phenyl and heteroaryl are each independentlyoptionally substituted with 1, 2, or 3 R⁸.

In some embodiments, the compound of Formula I is according to FormulaI(a) or Formula I(b):

optionally as a single stereoisomer or mixture of stereoisomers thereofand additionally optionally as a pharmaceutically acceptable saltthereof.

In some embodiments, the compound of Formula I is according to FormulaII, Formula II(a), or Formula II(b):

optionally as a single stereoisomer or mixture of stereoisomers thereofand additionally optionally as a pharmaceutically acceptable saltthereof.

In some embodiments, the compound of Formula I is according to FormulaIII, Formula III(a), or Formula III(b):

optionally as a single stereoisomer or mixture of stereoisomers thereofand additionally optionally as a pharmaceutically acceptable saltthereof.

In some embodiments, the compound of Formula I is according to FormulaIV, Formula IV(a), or Formula IV(b):

optionally as a single stereoisomer or mixture of stereoisomers thereofand additionally optionally as a pharmaceutically acceptable saltthereof.

In some embodiments, the compound of Formula I is according to FormulaV, Formula V(a), or Formula V(b):

optionally as a single stereoisomer or mixture of stereoisomers thereofand additionally optionally as a pharmaceutically acceptable saltthereof.

In some embodiments, the compound of Formula I is according to FormulaVI, Formula VI(a), or Formula VI(b):

optionally as a single stereoisomer or mixture of stereoisomers thereofand additionally optionally as a pharmaceutically acceptable saltthereof.

In some embodiments, the compound of Formula I is according to FormulaVII, Formula VII(a), or Formula VII(b):

optionally as a single stereoisomer or mixture of stereoisomers thereofand additionally optionally as a pharmaceutically acceptable saltthereof.

In some embodiments, the compound of Formula I is according to FormulaVIII, Formula VIII(a), or Formula VIII(b):

optionally as a single stereoisomer or mixture of stereoisomers thereofand additionally optionally as a pharmaceutically acceptable saltthereof.

In some embodiments, the compound of Formula I is according to FormulaIX, Formula IX(a), or Formula IX(b):

optionally as a single stereoisomer or mixture of stereoisomers thereofand additionally optionally as a pharmaceutically acceptable saltthereof.

In some embodiments, the compound of Formula I is according to FormulaX, Formula X(a), or Formula X(b):

optionally as a single stereoisomer or mixture of stereoisomers thereofand additionally optionally as a pharmaceutically acceptable saltthereof.

In some embodiments, the compound of Formula I is according to FormulaXI, Formula XI(a), or Formula XI(b):

optionally as a single stereoisomer or mixture of stereoisomers thereofand additionally optionally as a pharmaceutically acceptable saltthereof.

In some embodiments, the compound of Formula I is according to FormulaXII, Formula XII(a), or Formula XII(b):

optionally as a single stereoisomer or mixture of stereoisomers thereofand additionally optionally as a pharmaceutically acceptable saltthereof.

In some embodiments, the compound of Formula I is that wherein p is 0 or1.

In some embodiments, the compound of Formula I is that wherein q is 0.

In some embodiments, the compound of Formula I is according to FormulaXIII, Formula XIII(a) or Formula XIII(b):

wherein

-   n is 1 or 2;-   R¹ is H; or R¹ and R² together form —OCH₂CH₂O—;-   R² is C₃₋₆ cycloalkyloxy;-   R³ is H, Cl, or F;-   R⁴ is H or C₁₋₄ alkyl;-   R⁵ and R^(5A) are each independently H or C₁₋₄ alkyl;-   X is N or O, and when X is N, the dashed line is a bond to form a    double bond, and when X is O, the dashed line is not a bond to form    a single bond;-   Y is CH₂, CH(C₁₋₄ alkyl), C(C₁₋₄ alkyl)₂, or O; with the proviso    that X and Y are not both O;-   Ring A is phenylene, naphthylene, benzothiophenylene, indazolylene,    or quinolylene;-   R⁷ is Cl, F, C₁₋₆ alkyl, cyclohexylmethoxy, phenyl, or thienyl,    where the cyclohexylmethoxy, phenyl, and thienyl are each optionally    substituted with R⁸;-   R⁸ is Cl, F, or C₁₋₆ alkyl; and    optionally a single stereoisomer or mixture of stereoisomers thereof    and additionally optionally a pharmaceutically acceptable salt    thereof.

In some embodiments, the compound of Formula I is according to FormulaXIII, Formula XIII(a) or Formula XIII(b):

wherein

-   n is 1 or 2;-   R¹ is H; or R¹ and R² together form —OCH₂CH₂O—;-   R² is C₃₋₆ cycloalkyloxy;-   R³ is H, Cl, or F;-   R⁴ is H or C₁₋₄ alkyl;-   R⁵ and R^(5A) are each independently H or C₁₋₄ alkyl;-   X is N or O, and when X is N, the dashed line is a bond to form a    double bond, and when X is O, the dashed line is not a bond to form    a single bond;-   Y is CH₂, CH(C₁₋₄ alkyl), C(C₁₋₄ alkyl)₂, or O; with the proviso    that X and Y are not both O;-   Ring A is phenylene, naphthylene, benzothiophenylene, indazolylene,    or quinolylene;-   R⁷ is Cl, F, C₁₋₆ alkyl, phenyl, or thienyl, where the phenyl and    thienyl are each optionally substituted with R⁸;-   R⁸ is Cl, F, or C₁₋₆ alkyl; and    optionally a single stereoisomer or mixture of stereoisomers thereof    and additionally optionally a pharmaceutically acceptable salt    thereof.

In some embodiments, the compound of Formula XIII, Formula XIII(a) orFormula XIII(b) is that where the Ring A is phenylene, naphthylene orbenzothiophenylene. In some embodiments, the compound of Formula XIII,Formula XIII(a) or Formula XIII(b) is that where the Ring A isindazolylene or quinolylene.

In some embodiments, R¹ is H. In some embodiments, R¹ and R² togetherform —OCH₂CH₂O—.

In some embodiments, R³ is H. In some embodiments, R³ is halogen; or R³is Cl or F; or R³ is Cl; or R³ is F.

In some embodiments, R⁴ is H. In some embodiments, R⁴ is C₁₋₄ alkyl; orR⁴ is methyl, ethyl, propyl or butyl; or R⁴ is methyl, ethyl, or propyl;or R⁴ is methyl or ethyl; or R⁴ is methyl.

In some embodiments, R⁵ and R^(5A) are each H. In some embodiments, oneof R⁵ or R^(5A) is H and the other is C₁₋₄ alkyl; or the other ismethyl, ethyl, propyl or butyl; or the other is methyl, ethyl, orpropyl; or the other is methyl or ethyl; or the other is methyl. In someembodiments, both of R⁵ or R^(5A) are C₁₋₄ alkyl; or one is methyl orethyl and the other is methyl, ethyl, propyl or butyl; or one is methylor ethyl and the other is methyl, ethyl, or propyl; or one is methyl orethyl and the other is methyl or ethyl; or one is methyl and the otheris methyl or ethyl. In some embodiments, both of R⁵ or R^(5A) aremethyl.

In some embodiments, R⁷ at each occurrence is independently Cl, F, C₁₋₆alkyl, phenyl, or 5-6 membered heteroaryl, wherein the phenyl andheteroaryl are each optionally substituted with 1, 2, or 3 R⁸; or thephenyl and heteroaryl are each substituted with Cl or F. In someembodiments, R⁷ at each occurrence is independently Cl, F, methyl,ethyl, propyl, butyl, phenyl, or 5-6 membered heteroaryl, wherein thephenyl and heteroaryl are each substituted with R⁸; or the phenyl andheteroaryl are each substituted with Cl or F. In some embodiments, R⁷ ateach occurrence is independently Cl, F, methyl, phenyl, or 5 memberedheteroaryl, wherein the phenyl and heteroaryl are each substituted withR⁸; or the phenyl and heteroaryl are each substituted with Cl or F. Insome embodiments, R⁷ at each occurrence is independently Cl, F, methyl,phenyl, or thienyl, wherein the phenyl and thienyl are each substitutedwith R⁸. In some embodiments, R⁷ at each occurrence is independently Cl,F, methyl, phenyl, or thienyl, wherein the phenyl is substituted with Fand the thienyl is substituted with Cl. In some embodiments, R⁷ at eachoccurrence is independently Cl or F. In some embodiments, R⁷ at eachoccurrence is independently phenyl or thienyl, wherein the phenyl andthienyl are each substituted with R⁸. In some embodiments, R⁷ at eachoccurrence is independently phenyl or thienyl, wherein the phenyl andthienyl are each substituted with Cl or F. In some embodiments, R⁷ ateach occurrence is independently phenyl or thienyl, wherein the phenylis substituted with F and the thienyl is substituted with Cl.

In some embodiments, R⁷ at each occurrence is independently Cl, F, C₁₋₆alkyl, C₁₋₆ alkoxy, C₃₋₆ cycloalkyloxy, (C₃₋₆ cycloalkyl)C₁₋₆ alkoxy,phenyl, or 5-6 membered heteroaryl, wherein the cycloalkyloxy,(cycloalkyl)alkoxy, phenyl and heteroaryl are each optionallysubstituted with 1, 2, or 3 R⁸; or the cycloalkyloxy,(cycloalkyl)alkoxy, phenyl and heteroaryl are each optionallysubstituted with Cl or F. In some embodiments, R⁷ at each occurrence isindependently Cl, F, methyl, ethyl, propyl, butyl, C₃₋₆ cycloalkyloxy,(C₃₋₆ cycloalkyl)C₁₋₆ alkoxy, phenyl, or 5-6 membered heteroaryl,wherein the cycloalkyloxy, (cycloalkyl)alkoxy, phenyl and heteroaryl areeach optionally substituted with R⁸; or the cycloalkyloxy,(cycloalkyl)alkoxy, phenyl and heteroaryl are each optionallysubstituted with Cl or F. In some embodiments, R⁷ at each occurrence isindependently Cl, F, methyl, cycloalkyloxy, (cycloalkyl)alkoxy, phenyl,or 5 membered heteroaryl, wherein the cycloalkyloxy, (cycloalkyl)alkoxy,phenyl and heteroaryl are each optionally substituted with R⁸; or thecycloalkyloxy, (cycloalkyl)alkoxy, phenyl and heteroaryl are eachoptionally substituted with Cl or F. In some embodiments, R⁷ at eachoccurrence is independently Cl, F, methyl, cyclohexylmethoxy, phenyl, orthienyl, wherein the cyclohexylmethoxy, phenyl and thienyl are eachoptionally substituted with R⁸. In some embodiments, R⁷ at eachoccurrence is independently Cl, F, methyl, cyclohexylmethoxy, phenyl, orthienyl, wherein the cyclohexylmethoxy, phenyl and thienyl are eachsubstituted with R⁸. In some embodiments, R⁷ at each occurrence isindependently Cl, F, methyl, cyclohexylmethoxy, phenyl, or thienyl,wherein the cyclohexylmethoxy is unsubstituted, the phenyl issubstituted with F, and the thienyl is substituted with Cl. In someembodiments, R⁷ at each occurrence is independently Cl or F. In someembodiments, R⁷ at each occurrence is independently cyclohexylmethoxy,phenyl or thienyl, wherein the cyclohexylmethoxy is unsubstituted, andthe phenyl and thienyl are each substituted with R⁸. In someembodiments, R⁷ at each occurrence is independently cyclohexylmethoxy,phenyl or thienyl, wherein the cyclohexylmethoxy is unsubstituted, andthe phenyl and thienyl are each substituted with Cl or F. In someembodiments, R⁷ at each occurrence is independently cyclohexylmethoxy,phenyl or thienyl, wherein the cyclohexylmethoxy is unsubstituted, thephenyl is substituted with F, and the thienyl is substituted with Cl.

In some embodiments, R⁸ at each occurrence is independently halogen; orR⁸ at each occurrence is independently Cl or F. In some embodiments, R⁸at each occurrence is independently cyano, amino, C₁₋₆ alkylamino, C₁₋₆dialkylamino, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, aminocarbonyl,C₁₋₆ alkylaminocarbonyl, or C₁₋₆ dialkylaminocarbonyl. In someembodiments, R⁸ at each occurrence is independently amino, C₁₋₆alkylamino, C₁₋₆ dialkylamino, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,aminocarbonyl, C₁₋₆ alkylaminocarbonyl, or C₁₋₆ dialkylaminocarbonyl. Insome embodiments, R⁸ at each occurrence is independently amino, C₁₋₆alkylamino, C₁₋₆ dialkylamino, C₁₋₆ alkyl, C₁₋₆ alkoxy, or C₁₋₆haloalkoxy. In some embodiments, R⁸ at each occurrence is independentlyaminocarbonyl, C₁₋₆ alkylaminocarbonyl, or C₁₋₆ dialkylaminocarbonyl.

In some embodiments, X is N and the dashed line is a bond to form adouble bond. In some embodiments, the compound of Formula I is thatwhere X is O and the dashed line is not a bond to form a single bond.

In some embodiments, Y is C(R⁶)₂, where each R⁶ is H; or one R⁶ is H andthe other is C₁₋₄ alkyl; or each R⁶ is C₁₋₄ alkyl. In some embodiments,Y is C(R⁶)₂, where one R⁶ is H and the other is methyl. In someembodiments, Y is C(R⁶)₂, where R⁶ is methyl. In some embodiments, Y isO.

In some embodiments, the —Y—X═moiety comprises —O—N═, CH₂—N═,—CH(CH₃)—N═, or —C(CH₃)₂—N═. In some embodiments, the —Y—X═moietycomprises —O—N═. In some embodiments, the —Y—X═moiety comprises —CH₂—N═,—CH(CH₃)—N═, or —C(CH₃)₂—N═. In some embodiments, the —Y—X═moiety is—C(CH₃)₂—N═. In some embodiments, the —Y—X— moiety comprises —CH₂—O—,—CH(CH₃)—O—, or —C(CH₃)₂—O—. In some embodiments, the —Y—X— moietycomprises —CH₂—O—.

In some embodiments, Ring A is phenylene or naphthylene, where thephenylene is optionally substituted with phenyl or 5-6 memberedheteroaryl, where the phenyl and 5-6 membered heteroaryl are eachindependently optionally substituted with Cl or F; and the naphthyleneis optionally substituted with Cl or F. In some embodiments, Ring A isphenylene or naphthylene, where the phenylene is optionally substitutedwith phenyl or thienyl, where the phenyl and thienyl are eachindependently optionally substituted with Cl or F; and the naphthyleneis optionally substituted with Cl or F. In some embodiments, Ring A isphenylene or naphthylene, where the phenylene is optionally substitutedwith fluorophenyl or thienyl substituted with chloro, and thenaphthylene is optionally substituted with chloro or fluoro; or thenaphthylene is optionally substituted with fluoro.

In some embodiments, Ring A is phenylene substituted with phenyl or 5-6membered heteroaryl, where the phenyl or heteroaryl are optionallysubstituted with chloro or fluoro; or the phenyl is substituted withfluoro and the heteroaryl is optionally substituted with chloro. In someembodiments, Ring A is phenylene substituted with phenyl or 6 memberedheteroaryl, where the phenyl or heteroaryl are optionally substitutedwith chloro or fluoro; or the phenyl is substituted with fluoro and theheteroaryl is optionally substituted with chloro. In some embodiments,Ring A is phenylene substituted with phenyl or 5 membered heteroaryl,where the phenyl or heteroaryl are optionally substituted with chloro orfluoro; or the phenyl is substituted with fluoro and the heteroaryl isoptionally substituted with chloro. In some embodiments, Ring A isphenylene substituted with phenyl or thienyl, where the phenyl orthienyl are optionally substituted with chloro or fluoro. In someembodiments, Ring A is phenylene substituted with fluorophenyl orchlorothienyl. In some embodiments, Ring A is phenylene substituted withfluorophenyl. In some embodiments, Ring A is phenylene substituted withchlorothienyl.

In some embodiments, Ring A is phenylene, which is optionallysubstituted with 1 or 2 R⁷. In some embodiments, Ring A is phenylene,which is optionally substituted with 1 or 2 R⁷, where each R⁷, whenpresent, is independently selected from halogen, C₁₋₆ alkyl, phenyl, or5-6 membered heteroaryl, where each phenyl or 5-6 membered heteroaryl,when present, is optionally and independently substituted with 1, 2, or3 R⁸. In some embodiments, Ring A is phenylene which is optionallysubstituted with 1 or 2 R⁷, where each R⁷, when present, isindependently selected from halogen, C₁₋₆ alkyl, phenyl, or 5-6 memberedheteroaryl, where each phenyl or 5-6 membered heteroaryl, when present,is optionally and independently substituted with 1, 2, or 3 R⁸, whereeach R⁸, when present, is selected from halogen, cyano, amino, C₁₋₆alkylamino, C₁₋₆ dialkylamino, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,aminocarbonyl, C₁₋₆ alkylaminocarbonyl, or C₁₋₆ dialkylaminocarbonyl.

In some embodiments, Ring A is phenylene, which is optionallysubstituted with 1 or 2 R⁷. In some embodiments, Ring A is phenylene,which is optionally substituted with 1 or 2 R⁷, where each R⁷, whenpresent, is independently selected from halogen, C₁₋₆ alkyl, C₁₋₆alkoxy, C₃₋₆ cycloalkyloxy, (C₃₋₆ cycloalkyl)C₁₋₆ alkoxy, phenyl, or 5-6membered heteroaryl, where each C₃₋₆ cycloalkyloxy, (C₃₋₆cycloalkyl)C₁₋₆ alkoxy, phenyl, or 5-6 membered heteroaryl, whenpresent, is optionally and independently substituted with 1, 2, or 3 R⁸.In some embodiments, Ring A is phenylene which is optionally substitutedwith 1 or 2 R⁷, where each R⁷, when present, is independently selectedfrom halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₆ cycloalkyloxy, (C₃₋₆cycloalkyl)_(C)-6 alkoxy, phenyl, or 5-6 membered heteroaryl, where eachC₃₋₆ cycloalkyloxy, (C₃₋₆ cycloalkyl)C₁₋₆ alkoxy, phenyl, or 5-6membered heteroaryl, when present, is optionally and independentlysubstituted with 1, 2, or 3 R⁸, where each R⁸, when present, is selectedfrom halogen, cyano, amino, C₁₋₆ alkylamino, C₁₋₆ dialkylamino, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, aminocarbonyl, C₁₋₆alkylaminocarbonyl, or C₁₋₆ dialkylaminocarbonyl.

In some embodiments, Ring A is naphthylene substituted with halogen orC₁₋₆ alkyl. In some embodiments, Ring A is naphthylene substituted withCl, F, methyl, ethyl, propyl, or butyl. In some embodiments, Ring A isnaphthylene substituted with Cl, F, or methyl. In some embodiments, RingA is naphthylene substituted with Cl or F; or the naphthylene issubstituted with Cl; or the naphthylene is substituted with F.

In some embodiments, Ring A is naphthylene, which is optionallysubstituted with 1 or 2 R⁷. In some embodiments, Ring A is naphthylene,which is optionally substituted with 1 or 2 R⁷, where each R⁷, whenpresent, is independently selected from halogen, C₁₋₆ alkyl, phenyl, or5-6 membered heteroaryl, where each phenyl or 5-6 membered heteroaryl,when present, is optionally and independently substituted with 1, 2, or3 R⁸. In some embodiments, Ring A is naphthylene, which is optionallysubstituted with 1 or 2 R⁷, where each R⁷, when present, isindependently selected from halogen, C₁₋₆ alkyl, phenyl, or 5-6 memberedheteroaryl, where each phenyl or 5-6 membered heteroaryl, when present,is optionally and independently substituted with 1, 2, or 3 R⁸, whereeach R⁸, when present, is independently selected from halogen, cyano,amino, C₁₋₆ alkylamino, C₁₋₆ dialkylamino, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, aminocarbonyl, C₁₋₆ alkylaminocarbonyl, or C₁₋₆dialkylaminocarbonyl. In some embodiments, Ring A is 5-10 memberedheteroarylene, which is optionally substituted with 1 or 2 R⁷. In someembodiments, Ring A is 5-10 membered heteroarylene, where the 5-10membered heteroarylene is bicyclic with 1-3 nitrogen atoms, which isoptionally substituted with 1 or 2 R⁷. In some embodiments, Ring A is5-10 membered heteroarylene, where the 5-10 membered heteroarylene isbicyclic with 1-2 nitrogen atoms, which is optionally substituted with 1or 2 R⁷. In some embodiments, Ring A is 5-10 membered heteroarylene,where the 5-10 membered heteroarylene is selected from phenylene,naphthylene, benzothiophenylene, indazolylene, or quinolylene, which isoptionally substituted with 1 or 2 R⁷. In some embodiments, Ring A is5-10 membered heteroarylene, which is optionally substituted with 1 or 2R⁷, where each R⁷, when present, is independently selected from halogen,C₁₋₆ alkyl, phenyl, or 5-6 membered heteroaryl, where each phenyl or 5-6membered heteroaryl, when present, is optionally and independentlysubstituted with 1, 2, or 3 R⁸. In some embodiments, Ring A is 5-10membered heteroarylene, which is optionally substituted with 1 or 2 R⁷,where each R⁷, when present is independently selected from halogen, C₁₋₆alkyl, phenyl, or 5-6 membered heteroaryl, where each phenyl or 5-6membered heteroaryl, when present, is optionally and independentlysubstituted with 1, 2, or 3 R⁸, where each R⁸, when present, is selectedfrom halogen, cyano, amino, C₁₋₆ alkylamino, C₁₋₆ dialkylamino, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, aminocarbonyl, C₁₋₆alkylaminocarbonyl, or C₁₋₆ dialkylaminocarbonyl.

In some embodiments, Ring A is benzothiophenylene, indazolylene, orquinolylene substituted with halogen or C₁₋₆ alkyl. In some embodiments,Ring A is benzothiophenylene, indazolylene, or quinolylene, where thebenzothiophenylene is substituted with halogen, and the indazolylene orquinolylene are substituted with C₁₋₆ alkyl. In some embodiments, Ring Ais benzothiophenylene, indazolylene, or quinolylene, where thebenzothiophenylene is substituted with Cl or F, and the indazolylene orquinolylene are substituted with methyl, ethyl, propyl or butyl. In someembodiments, Ring A is benzothiophenylene, indazolylene, or quinolylene,where the benzothiophenylene is substituted with Cl or F, and theindazolylene or quinolylene are substituted with methyl. In someembodiments, Ring A is benzothiophenylene, indazolylene, or quinolylene,where the benzothiophenylene is substituted with Cl, and theindazolylene or quinolylene are substituted with methyl. In someembodiments, Ring A is benzothiophenylene substituted with Cl or F; orRing A is benzothiophenylene substituted with Cl. In some embodiments,Ring A is indazolylene or quinolylene, each optionally substituted withC₁₋₄ alkyl; or each is optionally substituted with methyl. In someembodiments, Ring A is indazolylene or quinolylene, where theindazolylene is substituted with methyl.

In some embodiments, Ring A is 5-6 membered heteroarylene or 9-10membered bicyclic heteroarylene, each of which is optionally substitutedwith halogen or C₁₋₆ alkyl. In some embodiments, Ring A is 5-6 memberedheteroarylene or 9-10 membered bicyclic heteroarylene, each of which issubstituted with Cl, F, methyl, ethyl, propyl or butyl. In someembodiments, Ring A is 5-6 membered heteroarylene substituted with Cl orF; or Ring A is 9-10 membered bicyclic heteroarylene substituted withmethyl, ethyl, propyl or butyl. In some embodiments, Ring A is 5-6membered heteroarylene substituted with Cl, or Ring A is 9-10 memberedbicyclic heteroarylene substituted with methyl. In some embodiments,Ring A is 5 membered heteroarylene substituted with Cl, or Ring A is9-10 membered bicyclic heteroarylene substituted with methyl. In someembodiments, Ring A is thienyl substituted with Cl; indazolylenesubstituted with methyl; or quinolylene.

In some embodiments, Ring A is 5-6 membered heteroarylene optionallysubstituted with halogen or C₁₋₆ alkyl; or Ring A is 5 memberedheteroarylene optionally substituted with halogen or C₁₋₆ alkyl; or RingA is 6 membered heteroarylene optionally substituted with halogen orC₁₋₆ alkyl. In some embodiments, Ring A is 5-6 membered heteroarylenesubstituted with Cl, F, methyl, ethyl, propyl or butyl; or Ring A is 5membered heteroarylene substituted with Cl, F, methyl, ethyl, propyl orbutyl; or Ring A is 6 membered heteroarylene substituted with Cl, F,methyl, ethyl, propyl or butyl. In some embodiments, Ring A is 5-6membered heteroarylene substituted with Cl or F; or Ring A is 5 memberedheteroarylene substituted with Cl or F; or Ring A is 6 memberedheteroarylene substituted with Cl or F. In some embodiments, Ring A is5-6 membered heteroarylene substituted with Cl; or Ring A is 5 memberedheteroarylene substituted with Cl. In some embodiments, Ring A isthienyl substituted with Cl.

In some embodiments, Ring A is 9-10 membered bicyclic heteroaryleneoptionally substituted with halogen or C₁₋₆ alkyl; or Ring A is 9-10membered bicyclic heteroarylene with 1 or 2 ring nitrogen atomsoptionally substituted with halogen or C₁₋₆ alkyl; or Ring A is 9-10membered bicyclic heteroarylene with 2 ring nitrogen atoms optionallysubstituted with halogen or C₁₋₆ alkyl; or Ring A is 9-10 memberedbicyclic heteroarylene with 1 ring nitrogen atom optionally substitutedwith halogen or C₁₋₆ alkyl. In some embodiments, Ring A is 9-10 memberedbicyclic heteroarylene substituted with Cl, F, methyl, ethyl, propyl orbutyl; or Ring A is 9-10 membered bicyclic heteroarylene with 1 or 2ring nitrogen atoms substituted with Cl, F, methyl, ethyl, propyl orbutyl; or Ring A is 9-10 membered bicyclic heteroarylene with 2 ringnitrogen atoms substituted with Cl, F, methyl, ethyl, propyl or butyl;or Ring A is 9-10 membered bicyclic heteroarylene with 1 ring nitrogenatom substituted with Cl, F, methyl, ethyl, propyl or butyl. In someembodiments, Ring A is 9-10 membered bicyclic heteroarylene substitutedwith methyl, ethyl, propyl or butyl; or Ring A is 9-10 membered bicyclicheteroarylene with 1 or 2 ring nitrogen atoms substituted with methyl,ethyl, propyl or butyl; or Ring A is 9-10 membered bicyclicheteroarylene with 2 ring nitrogen atoms substituted with methyl, ethyl,propyl or butyl; or Ring A is 9-10 membered bicyclic heteroarylene with1 ring nitrogen atom substituted with methyl, ethyl, propyl or butyl. Insome embodiments, Ring A is 9-10 membered bicyclic heteroarylenesubstituted with methyl; or Ring A is 9-10 membered bicyclicheteroarylene with 1 or 2 ring nitrogen atoms substituted with methyl;or Ring A is 9-10 membered bicyclic heteroarylene with 2 ring nitrogenatoms substituted with methyl; or Ring A is 9-10 membered bicyclicheteroarylene with 1 ring nitrogen atom substituted with methyl. In someembodiments, Ring A is indazolylene substituted with methyl, or Ring Ais quinolylene.

In some embodiments, Ring A is benzothiophenylene substituted with Cl orF; Ring A is benzothiophenylene substituted with Cl.

In some embodiments, Ring A is indazolylene or quinolylene, eachoptionally substituted with C₁₋₆ alkyl; or Ring A is indazolylene orquinolylene, each optionally substituted with methyl, ethyl, propyl orbutyl; or Ring A is indazolylene or quinolylene, each optionallysubstituted with methyl. In some embodiments, Ring A is indazolylenesubstituted with methyl, or Ring A is quinolylene. In some embodiments,Ring A is quinolylene.

In some embodiments, Ring A is indazolylene substituted with C₁₋₆ alkyl;or Ring A is indazolylene substituted with methyl, ethyl, propyl orbutyl. In some embodiments, Ring A is indazolylene substituted withmethyl.

In some embodiments, Ring B is a 4-6 membered heterocycloalkyl ring,which is optionally substituted with 1, 2, 3, or 4 R⁹. In someembodiments, Ring B is a 4-6 membered heterocycloalkyl ring, where the4-6 membered heterocycloalkyl ring is a 4-6 membered heteroalkyl ringwith one nitrogen atom, which is optionally substituted with 1, 2, 3, or4 R⁹. In some embodiments, Ring B is a 4-6 membered heterocycloalkylring, where the 4-6 membered heterocycloalkyl ring is a 4-6 memberedheteroalkyl ring with one nitrogen atom, which is optionally substitutedwith 1, 2, 3, or 4 R⁹, where each R⁹, when present, is independentlyselected from halogen, OR¹⁰, or N(R¹⁰)₂. In some embodiments, Ring B isa 4-6 membered heterocycloalkyl ring, where the 4-6 memberedheterocycloalkyl ring is a 4-6 membered heteroalkyl ring with onenitrogen atom, which is optionally substituted with 1, 2, 3, or 4 R⁹,where each R⁹, when present, is independently selected from halogen,OR¹⁰, or N(R¹⁰)₂, where each R¹⁰, when present, is independentlyselected from H or C₁₋₄ alkyl.

In some embodiments, Ring B is a 4-6 membered heterocycloalkyl ring,which is optionally substituted with 1 or 2 R⁹. In some embodiments,Ring B is a 4-6 membered heterocycloalkyl ring, which is optionallysubstituted with 1 or 2 groups independently selected from Cl, F, C₁₋₄alkoxy, amino, C₁₋₆ alkylamino, and C₁₋₆ dialkylamino. In someembodiments, Ring B is a 4-6 membered heterocycloalkyl ring, which isoptionally substituted with 1 or 2 groups independently selected from Cland F. In some embodiments, Ring B is a 4-6 membered heterocycloalkylring, which is optionally substituted with 1 or 2 groups independentlyselected from C₁₋₄ alkoxy, amino, C₁₋₆ alkylamino, and C₁₋₆dialkylamino.

In some embodiments, Ring B is an azetidine ring, which is optionallysubstituted with 1 or 2 groups independently selected from Cl, F, C₁₋₄alkoxy, amino, C₁₋₆ alkylamino, and C₁₋₆ dialkylamino. In someembodiments, Ring B is an azetidine ring, which is optionallysubstituted with 1 or 2 groups independently selected from Cl and F. Insome embodiments, Ring B is an azetidine ring, which is optionallysubstituted with 1 or 2 groups independently selected from C₁₋₄ alkoxy,amino, C₁₋₆ alkylamino, and C₁₋₆ dialkylamino. In some embodiments, RingB is an unsubstituted azetidine ring.

In some embodiments, Ring B is a pyrrolidine ring, which is optionallysubstituted with 1 or 2 groups independently selected from Cl, F, C₁₋₄alkoxy, amino, C₁₋₆ alkylamino, and C₁₋₆ dialkylamino. In someembodiments, Ring B is a pyrrolidine ring, which is optionallysubstituted with 1 or 2 groups independently selected from Cl and F. Insome embodiments, Ring B is a pyrrolidine ring, which is optionallysubstituted with 1 or 2 groups independently selected from C₁₋₄ alkoxy,amino, C₁₋₆ alkylamino, and C₁₋₆ dialkylamino. In some embodiments, RingB is a unsubstituted pyrrolidine ring.

In some embodiments, Ring B is a piperidine ring, which is optionallysubstituted with 1 or 2 groups independently selected from Cl, F, C₁₋₄alkoxy, amino, C₁₋₆ alkylamino, and C₁₋₆ dialkylamino. In someembodiments, Ring B is a piperidine ring, which is optionallysubstituted with 1 or 2 groups independently selected from Cl and F. Insome embodiments, Ring B is a piperidine ring, which is optionallysubstituted with 1 or 2 groups independently selected from C₁₋₄ alkoxy,amino, C₁₋₆ alkylamino, and C₁₋₆ dialkylamino. In some embodiments, RingB is an unsubstituted piperidine ring.

In some embodiments, the compound of Formula I is according to FormulaXIV:

where all groups are as defined in any of the embodiments describedherein.

In some embodiments, the compound of Formula I is according to FormulaXV:

where all groups are as defined in any of the embodiments describedherein.

In some embodiments, the compound of Formula I is according to FormulaXVI:

where all groups are as defined in any of the embodiments describedherein.

In some embodiments, the compound of Formula I is according to FormulaXVII:

where all groups are as defined in any of the embodiments describedherein.

In some embodiments, the compound of Formula I is according to FormulaXVIII:

where all groups are as defined in any of the embodiments describedherein.

In some embodiments, the compound of Formula I is according to FormulaXIX:

where all groups are as defined in any of the embodiments describedherein.

In some embodiments, the compound of Formula I is according to FormulaXX:

where all groups are as defined in any of the embodiments describedherein.

In some embodiments, the compound of Formula I is according to FormulaXXI:

where all groups are as defined in any of the embodiments describedherein.

In some embodiments, the compound of Formula I is according to FormulaXXII:

where all groups are as defined in any of the embodiments describedherein.

In some embodiments, the compound of Formula I is according to FormulaXXIII:

where all groups are as defined in any of the embodiments describedherein.

In some embodiments, the compound of Formula I is that wherein Ring Ais:

wherein Ring A is optionally independently substituted 0, 1, or 2 R⁷;and wherein the asterix indicates the point of attachment to the rest ofthe molecule.

In some embodiments, the compound of Formula I is that wherein

wherein the asterix indicates the point of attachment to the rest of themolecule.

In some embodiments, the compound of Formula I is that wherein

wherein the asterix indicates the point of attachment to the rest of themolecule.

In some embodiments, the compound of Formula I is according to thecompounds in Table 1, where the compound nomenclature was generated bythe ChemBioDraw 14.0 program:

TABLE 1 Example No. Name Structure 1 N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- (pyrrolidin-1-yl)propan-2-yl)-7-(4-fluorophenyl)-1H- benzo[d][1,2]oxazine-4-carboxamide

2 N-((1R,2R)-1-(4-cyclopropoxy-3- fluorophenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-7-(4-fluorophenyl)- 1H-benzo[d][1,2]oxazine-4-carboxamide

3 N-((1R,2R)-1-(8-fluoro-2,3- dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2- yl)-7-(4-fluorophenyl)-1H-benzo[d][1,2]oxazine-4-carboxamide

4 N-((1R,2R)-1-(4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2- yl)-7-(4-fluorophenyl)-1H-benzo[d][1,2]oxazine-4-carboxamide

5 N-((1R,2R)-3-(azetidin-1-yl)-1-(3- chloro-4-cyclopropoxyphenyl)-1-hydroxypropan-2-yl)-7-(4- fluorophenyl)-1H-benzo[d][1,2]oxazine-4-carboxamide

6 N-((1R,2R)-3-(azetidin-1-yl)-1-(4-cyclopropoxyphenyl)-1-hydroxypropan- 2-yl)-7-(4-fluorophenyl)-1H-benzo[d][1,2]oxazine-4-carboxamide

7 N-((1R,2R)-3-(azetidin-1-yl)-1-(4- cyclopropoxy-3-fluorophenyl)-1-hydroxypropan-2-yl)-7-(4- fluorophenyl)-1H-benzo[d][1,2]oxazine-4-carboxamide

8 7-(5-chlorothiophen-2-yl)-N-((1R,2R)-1-(4-cyclopropoxy-3-fluorophenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2- yl)-1H-benzo[d][1,2]oxazine-4-carboxamide

9 N-((1R,2R)-3-(azetidin-1-yl)-1-(4- cyclopropoxy-3-fluorophenyl)-1-hydroxypropan-2-yl)-7-(5- chlorothiophen-2-yl)-1H-benzo[d][1,2]oxazine-4-carboxamide

10 N-((1R,2R)-1-(3-chloro-4- cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-7-(5- chlorothiophen-2-yl)-1H-benzo[d][1,2]oxazine-4-carboxamide

11 N-((1R,2R)-3-(azetidin-1-yl)-1-(4-cyclopropoxyphenyl)-1-hydroxypropan- 2-yl)-7-(5-chlorothiophen-2-yl)-1H-benzo[d][1,2]oxazine-4-carboxamide

12 7-chloro-N-((1R,2R)-1-(4- cyclopropoxy-3-fluorophenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2- yl)-1H-benzo[4,5]thieno[2,3-d][1,2]oxazine-4-carboxamide

13 7-chloro-N-((1R,2R)-1-(3-chloro-4- cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-1H- benzo[4,5]thieno[2,3-d][1,2]oxazine-4-carboxamide

14 7-(5-chlorothiophen-2-yl)-N-((1R,2R)-1-(4-cyclopropoxyphenyl)-1-hydroxy-3- (pyrrolidin-1-yl)propan-2-yl)-1H-benzo[d][1,2]oxazine-4-carboxamide

15 N-((1R,2R)-3-(azetidin-1-yl)-1-(4- cyclopropoxy-3-fluorophenyl)-1-hydroxypropan-2-yl)-7-chloro-1H- benzo[4,5]thieno[2,3-d][1,2]oxazine-4-carboxamide

16 N-((1R,2R)-3-(azetidin-1-yl)-1-(3- chloro-4-cyclopropoxyphenyl)-1-hydroxypropan-2-yl)-7-chloro-1H- benzo[4,5]thieno[2,3-d][1,2]oxazine-4-carboxamide

17 N-((1R,2R)-1-(4-cyclopropoxy-3-fluorophenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-7-(4-fluorophenyl)-N-methyl-1H-benzo[d][1,2]oxazine-4- carboxamide

18 7-(5-chlorothiophen-2-yl)-N-((1R,2R)-1-(4-cyclopropoxy-3-fluorophenyl)-1-hydrdoxy-3-(pyrrolidin-1-yl)propan-2-yl)-N-methyl-1H-benzo[d][1,2]oxazine- 4-carboxamide

19 N-((1R,2R)-1-(3-chloro-4- cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-7-(4- fluorophenyl)-N-methyl-1H-benzo[d][1,2]oxazine-4-carboxamide

20 N-((1R,2R)-1-(3-chloro-4- cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-1H- naphtho[2,3-d][1,2]oxazine-4-carboxamide

21 N-((1R,2R)-3-(azetidin-1-yl)-1-(3- chloro-4-cyclopropoxyphenyl)-1-hydroxypropan-2-yl)-7-(4- fluorophenyl)-N-methyl-1H-benzo[d][1,2]oxazine-4-carboxamide

22 N-((1R,2R)-1-(3-chloro-4- cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-1H- naphtho[2,1-d][1,2]oxazine-4-carboxamide

23 N-((1R,2R)-1-(3-chloro-4- cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-7-(4- fluorophenyl)-1,1-dimethyl-1H-benzo[d][1,2]oxazine-4-carboxamide

24 N-((1R,2R)-1-(3-chloro-4- cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-7-(4- fluorophenyl)-1-methyl-1H-benzo[d][1,2]oxazine-4-carboxamide

25 N-((1R,2R)-1-(4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-1H-naphtho[2,1-d][1,2]oxazine-4- carboxamide

26 N-((1R,2R)-3-(azetidin-1-yl)-1-(3- chloro-4-cyclopropoxyphenyl)-1-hydroxypropan-2-yl)-1H-naphtho[2,1- d][1,2]oxazine-4-carboxamide

27 N-((1R,2R)-1-(3-chloro-4- cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-10H- [1,2]oxazino[4,5-h]quinoline-7-carboxamide

28 N-((1R,2R)-1-(3-chloro-4- cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-8-fluoro- 1H-naphtho[2,1-d][1,2]oxazine-4-carboxamide

29 N-((1R,2R)-1-(4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2- yl)-8-fluoro-1H-naphtho[2,1-d][1,2]oxazine-4-carboxamide

30 N-((1R,2R)-3-(azetidin-1-yl)-1-(3- chloro-4-cyclopropoxyphenyl)-1-hydroxypropan-2-yl)-8-fluoro-1H- naphtho[2,1-d][1,2]oxazine-4-carboxamide

31 N-((1R,2R)-3-(azetidin-1-yl)-1-(4-cyclopropoxyphenyl)-1-hydroxypropan- 2-yl)-8-fluoro-1H-naphtho[2,1-d][1,2]oxazine-4-carboxamide

32 8-chloro-N-((1R,2R)-1-(3-chloro-4- cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-1H- thieno[3′,2′:3,4]benzo[1,2-d][1,2]oxazine-4-carboxamide

33 N-((1R,2R)-1-(3-chloro-4- cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-7-methyl- 1,7-dihydro-[1,2]oxazino[5,4-e]indazole-4-carboxamide

34 N-((1R,2R)-1-(3-chloro-4- cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-1-methyl- 1,9-dihydro-[1,2]oxazino[4,5-g]indazole-6-carboxamide

35 N-((1R,2R)-1-(3-chloro-4- cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-methyl- 2,9-dihydro-[1,2]oxazino[4,5-g]indazole-6-carboxamide

36 N-((1R,2R)-1-(3-chloro-4- cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-1H- [1,2]oxazino[5,4-f]quinoline-4-carboxamide

37 2-chloro-N-((1R,2R)-1-(3-chloro-4- cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-9H- thieno[2′,3′:3,4]benzo[1,2-d][1,2]oxazine-6-carboxamide

38 N-((1R,2R)-1-(4-cyclopropoxy-3-fluorophenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-6-(4-fluorophenyl)-3,4-dihydroisoquinoline-1-carboxamide

39 N-((1R,2R)-1-(3-chloro-4- cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-6-(4- fluorophenyl)-N-methyl-3,4-dihydroisoquinoline-1-carboxamide

40 N-((1R,2R)-3-(azetidiin-1-yl)-1-(4-cyclopropoxyphenyl)-1-hydroxypropan- 2-yl)-6-(4-fluorophenyl)-3,4-dihydroisoquinoline-1-carboxamide

41 N-((1R,2R)-1-(3-chloro-4- cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-6-(4- fluorophenyl)-3,3-dimethyl-3,4-dihydroisoquinoline-1-carboxamide

42 N-((1R,2R)-1-(3-chloro-4- cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-6-(4- fluorophenyl)isochroman-1-carboxamide

43 7-chloro-N-((1R,2R)-1-(3-chloro-4- cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3,4- dihydro-1H-benzo[4,5]thieno[2,3-c]pyran-1-carboxamide

44 8-chloro-N-((1R,2R)-1-(4- cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-1H- thieno[3′,2′:3,4]benzo[1,2-d][1,2]oxazine-4-carboxamide

45 N-((1R,2R)-1-(3-chloro-4- cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-7- (cyclohexylmethoxy)-1H-benzo[d][1,2]oxazine-4-carboxamide

46 N-((1R,2R)-1-(4-cyclopropoxy-3-fluorophenyl)-1-hydroxy-3-(pyrrolidin- 1-yl)propan-2-yl)-1-methyl-1,9-dihydro-[1,2]oxazino[4,5-g]indazole-6- carboxamide

47 2-chloro-N-((1R,2R)-1-(4- cyclopropoxy-3-fluorophenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2- yl)-9H-thieno[2′,3′:3,4]benzo[1,2-d][1,2]oxazine-6-carboxamide

In some embodiments, the compound is selected from Table 1.

In some embodiments, the compound is selected from the group consistingof the compounds of Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, and 43.

In some embodiments, the compound is selected from the group consistingof the compounds of Examples 44, 45, 46, and 47.

In some embodiments, the compound is selected from the group consistingof the compounds of Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 17, 18, 19, 20, 21, 22, 24, 25, 26, 27, 28, 29, 30, 31, 38, 39, 40,44, 45, 46, and 47.

In some embodiments, the compound is selected from the group consistingof the compounds of Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 14, 17,18, 19, 20, 21, 22, 25, 26, 27, 28, 29, 30, 38, 39, 44, 46, and 47.

In some embodiments, the compound is selected from the group consistingof the compounds of Examples 1, 2, 3, 7, 8, 9, 14, 17, 20, 22, 25, 26,27, 28, 29, 30, 45, 46, and 47.

In some embodiments, the compound is selected from the group consistingof the compounds of Examples 1, 2, 3, 4, 5, 6, 7, 17, 19, 21, 23, 24,38, 39, 40, 41, and 42.

In some embodiments, the compound is selected from the group consistingof the compounds of Examples 8, 9, 10, 11, 14, and 18.

In some embodiments, the compound is selected from the group consistingof the compounds of Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 14, 17,18, 19, 21, 23, 24, 38, 39, 40, 41, 42, and 45.

In some embodiments, the compound is selected from the group consistingof the compounds of Examples 12, 13, 15, 16, 44 and 47.

In some embodiments, the compound is selected from the group consistingof the compounds of Examples 20, 22, 25, 26, 28, 29, 30, and 31.

In some embodiments, the compound is selected from the group consistingof the compounds of Examples 27, 32, 33, 34, 35, 36, 37, 43, 44, 46, and47.

In some embodiments, the compound is selected from the group consistingof the compounds of Examples 1, 2, 3, 4, 8, 10, 12, 13, 14, 17, 18, 19,20, 22, 23, 24, 25, 27, 28, 29, 32, 33, 34, 35, 36, 37, 38, 39, 41, 42,43, 44, 45, 46, and 47.

In some embodiments, the compound is selected from the group consistingof the compounds of Examples 5, 6, 7, 9, 11, 15, 16, 21, 26, 30, 31, and40.

In some embodiments, the compound is selected from the group consistingof the compounds of Examples 1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, and 47.

In some embodiments, the compound is selected from the compound ofExample 3.

In some embodiments, the compound is selected from the group consistingof the compounds of Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34, 35, 36, 37, 44, 45, 46, and 47.

In some embodiments, the compound is selected from the group consistingof the compounds of Examples 38, 39, 40, 41, 42, and 43.

In some embodiments, the compound is selected from the group consistingof the compounds of Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 19, 20, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,35, 36, 37, 38, 40, 41, 42, 43, 44, 45, 46, and 47.

In some embodiments, the compound is selected from the group consistingof the compounds of Examples 17, 18, 19, 21, and 38.

Pharmaceutical Administration and Formulation

In some embodiments, provided herein are pharmaceutical compositionscomprising a Compound of Formula I, I(b), I(c), or a compound in Table1, optionally as a single stereoisomer or mixture of stereoisomersthereof and additionally optionally as a pharmaceutically acceptablesalt thereof; and a pharmaceutically acceptable excipient.

In some embodiments, the pharmaceutical composition comprises a compoundof Formula I, I(a), I(b), II, II(a), II(b), III, III(a), III(b), IV,IV(a), IV(b), V, V(a), V(b), VI, VI(a), VI(b), VII, VII(a), VII(b),VIII, VIII(a), VIII(b), IX, IX(a), IX(b), X, X(a), X(b), XI, XI(a),XI(b), XII, XII(a), XII(b), XIII, XIII(a), XIII(b), XIV, XV, XVI, XVII,XVIII, XIX, XX, XXI, XXII, XXIII or a compound of Table 1; optionally asa single stereoisomer or mixture of stereoisomers thereof andadditionally optionally as a pharmaceutically acceptable salt thereof;and one or more pharmaceutically acceptable excipient(s).

In certain embodiments, the compounds presented herein can beadministered to subject in need thereof by any accepted route ofadministration. Acceptable routes of administration include, but are notlimited to, buccal, cutaneous, endocervical, endosinusial, endotracheal,enteral, epidural, interstitial, intra-abdominal, intra-arterial,intrabronchial, intrabursal, intracerebral, intracisternal,intracoronary, intradermal, intraductal, intraduodenal, intradural,intraepidermal, intraesophageal, intragastric, intragingival,intraileal, intralymphatic, intramedullary, intrameningeal,intramuscular, intraovarian, intraperitoneal, intraprostatic,intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular,intrathecal, intratubular, intratumor, intrauterine, intravascular,intravenous, nasal, nasogastric, oral, parenteral, percutaneous,peridural, rectal, respiratory (inhalation), subcutaneous, sublingual,submucosal, topical, transdermal, transmucosal, transtracheal, ureteral,urethral and vaginal.

In certain embodiments, the compounds presented herein can beadministered in any acceptable solid, semi-solid, liquid or gaseousdosage form. Acceptable dosage forms include, but are not limited to,aerosols, capsules, creams, elixirs, emulsions, gases, gels, grains,liniments, lotions, lozenges, ointments, pastes, powders, solutions,suspensions, syrups and tablets. Acceptable delivery systems include,but are not limited to, biodegradable implants (e.g., poly(DL-lactide),lactide/glycolide copolymers and lactide/caprolactone copolymers),capsules, douches, enemas, inhalers, intrauterine devices, nebulizers,patches, pumps and suppositories. Methods for preparing the dosage formsof the invention are known, or will be apparent, to those skilled inthis art; for example, see Remington's Pharmaceutical Sciences, 18thEd., (Mack Publishing Company, Easton, Pa., 1990).

In certain embodiments, a dosage form of the invention may be comprisedsolely of a compound of the invention or the compound of the inventionmay be formulated along with conventional excipients, includingpharmaceutical carriers, adjuvants, and/or other medicinal orpharmaceutical agents. Acceptable excipients include, but are notlimited to, (a) antiadherents, such as croscarmellose sodium,crosprovidone, sodium starch glycolate, microcrystalline cellulose,starch and talc; (b) binders, such as acacia, cellulose, gelatin,hydroxypropyl cellulose, lactose, maltitol, polyethylene glycol,polyvinyl pyrrolidone, sorbitol, starch, sugar, sucrose and xylitol; (c)coatings, such as cellulose, shellac, zein and enteric agents; (d)disintegrants, such as cellulose, crosslinked polyvinyl pyrrolidone,sodium carboxymethyl cellulose, methylcellulose, microcrystallinecellulose, sodium starch glycolate, starch, and alginic acid; (e)diluents or filling agents, such as calcium or sodium carbonate, calciumor sodium phosphate, sugars (such as glucose, lactose, mannitol,sorbitol and sucrose), cellulose, croscarmellose sodium, and povidone;(f) flavoring agents; (g) coloring agents; (h) glidants, such as calciumstearate, colloidal silicon dioxide, glyceryl behenate, glycerylmonostearate, glyceryl palmitostearate, hydrogenated vegetable oil,magnesium stearate, magnesium trisilicate, mineral oil, polyethyleneglycols, silicon dioxide, starch, stearate, stearic acid, talc, sodiumstearyl fumarate, sodium benzoate and zinc; (i) lubricants, such ascalcium stearate, hydrogenated vegetable oils, magnesium stearate,mineral oil, polyethylene glycol, sodium stearyl fumarate, stearin,stearic acid and talc; and (j) preservatives, such as chlorobutanol,citric acid, cysteine, methionine, methyl paraben, phenol, propylparaben, retinyl palmitate, selenium, sodium citrate, sorbic acid,vitamin A, vitamin C and vitamin E. Tablets may be uncoated or may becoated by known techniques including microencapsulation to delaydisintegration and adsorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearatealone or with a wax may be employed. Capsules may contain any of theexcipients listed above, and may additionally contain a semi-solid orliquid carrier, such as a polyethylene glycol or oil. Pharmaceuticalcarriers include soluble polymers, microparticles made of insoluble orbiodegradable natural and synthetic polymers, microcapsules ormicrospheres, lipoproteins, liposomes and micelles.

In certain embodiments, the pharmaceutical compositions may be in theform of a liquid, such as a solution, suspension, emulsion, syrup,elixir, or other like forms or may be presented as a dry product forreconstitution with water or other suitable vehicle before use. Liquidpreparations may contain conventional additives such as (a) liquiddiluents, such as water, saline, Ringer's solution, alcohols includingmonohydric alcohols and polyhydric alcohols such as polyethylene orpropylene glycols and their derivatives, glycerin, fixed oils such assynthetic mono or diglycerides, or other solvents; (b) surfactants,suspending agents, or emulsifying agents, such as sodiumcarboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose,sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia,polyoxyethylene sorbitan fatty acid esters, saturated polyglycolizedglycerides, monoglycerides, fatty acid esters, block copolymers ofethylene oxide and propylene oxide, polyoxyl stearates, ethoxylatedcastor oils, and ethoxylated hydroxystearic acids; (c) buffers, such asacetates, citrates or phosphates; (d) chelating agents, such asethylenediaminetetraacetic acid, carbohydrates such as dextran,hydroxyalkylcellulose, hydroxyalkylmethylcellulose, or saturated fattyacids, such as stearic acid; (e) antibacterial agents, such aschlorobutanol, benzyl alcohol, phenol, sorbic acid, or parabens, such asmethyl paraben; (f) antioxidants, such as ascorbic acid or sodiumbisulfite; (g) isotonic agents, sodium chloride or sugars, such asdextrose; as well as sweetening and flavoring agents, dyes andpreservatives.

In certain embodiments, the pharmaceutical compositions may be in theform of a sterile injectable preparation, such as a sterile injectableaqueous or oleaginous suspension. This suspension may be formulatedaccording to the known art using those suitable dispersing or wettingagents and suspending agents which have been mentioned above. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally acceptable diluent or solvent,such as a solution in 1,3-butane-diol or prepared as a lyophilizedpowder. Among the acceptable vehicles and solvents that may be employedare water, Ringer's solution and isotonic sodium chloride solution. Inaddition, sterile fixed oils may conventionally be employed as a solventor suspending medium. For this purpose any bland fixed oil may beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid may likewise be used in the preparation ofinjectables.

In certain embodiments, the pharmaceutical compositions will contain atherapeutically effective amount of a compound of the invention, as anindividual stereoisomer or mixture of stereoisomers, or apharmaceutically acceptable salt thereof, with the remainder of thepharmaceutical composition comprised of one or more pharmaceuticallyacceptable excipients. Generally, for oral administration, a compound ofthe invention, as an individual stereoisomer or mixture ofstereoisomers, or a pharmaceutically acceptable salt thereof willcomprise from 1% to 99% by weight of a pharmaceutically acceptablecomposition, with the remainder of the composition comprised of one ormore pharmaceutically acceptable excipients. Typically, a compound ofthe invention, as an individual stereoisomer or mixture ofstereoisomers, or a pharmaceutically acceptable salt thereof willcomprise from 5% to 75% by weight of a pharmaceutically acceptablecomposition, with the remainder of the composition comprised of one ormore pharmaceutically acceptable excipients. For parenteraladministration, a compound of the invention, as an individualstereoisomer or mixture of stereoisomers, or a pharmaceuticallyacceptable salt thereof will comprise from 0.01% to 1% by weight of apharmaceutically acceptable composition.

In certain embodiments, a therapeutically effective amount of a compoundof the invention will vary depending upon a sundry of factors includingthe activity, metabolic stability, rate of excretion and duration ofaction of the compound, the age, weight, general health, sex, diet andspecies of the subject, the mode and time of administration of thecompound, the presence of adjuvants or additional therapeutically activeingredients in a composition, and the severity of the disease for whichthe therapeutic effect is sought.

In certain embodiments, the compounds presented herein can beadministered to human subjects at dosage levels in the range of about0.1 to about 10,000 mg per day. A normal human adult having a bodyweight of about 70 kilograms can be administered a dosage in the rangeof from about 0.15 μg to about 150 mg per kilogram of body weight perday. Typically, a normal adult human will be administered from about 0.1mg to about 25 mg, or 0.5 mg to about 10 mg per kilogram of body weightper day. The compounds of the invention may be administered in one ormore unit dose forms. The unit doses may be administered one to fourtimes a day, or two times a day, or once a day. In an alternate methodof describing an effective dose, an oral unit dose is one that isnecessary to achieve a blood serum level of about 0.05 to 20 μg/ml orabout 1 to 20 μg/ml in a subject The optimum dose of a compound of theinvention for a particular subject can be determined by one of ordinaryskill in the art.

Uses and Methods of Treatment

In some embodiments, the compounds described herein are used in thepreparation or manufacture of medicaments for the treatment of diseasesor conditions that are mediated by the enzyme GCS or in which inhibitionof the enzyme GCS ameliorates the disease or condition. In someembodiments, a method for treating any of the diseases or conditionsdescribed herein in a subject in need of such treatment, involvesadministration of pharmaceutical compositions containing at least onecompound described herein, or a pharmaceutically acceptable salt,pharmaceutically active metabolite, pharmaceutically acceptable prodrug,or pharmaceutically acceptable solvate thereof, in therapeuticallyeffective amounts to said subject.

In some embodiments, provided is a method of treating or ameliorating amedical condition, comprising administering to a subject in need thereofa compound according to any of the various embodiments described hereinor a pharmaceutical composition according to any of the variousembodiments described herein.

In some embodiments, provided herein is a method of treating orameliorating a disease ameliorated by the inhibition of GCS comprisingadministering to a subject in need of treatment atherapeutically-effective amount of a compound of Formula I, I(a), I(b),II, II(a), II(b), III, III(a), III(b), IV, IV(a), IV(b), V, V(a), V(b),VI, VI(a), VI(b), VII, VII(a), VII(b), VIII, VIII(a), VIII(b), IX,IX(a), IX(b), X, X(a), X(b), XI, XI(a), XI(b), XII, XII(a), XII(b),XIII, XIII(a), XIII(b), XIV, XV, XVI, XVII, XVIII, XVIII, XIX, XX, XXI,XXII, XXIII, or a compound in Table 1; optionally as a singlestereoisomer or mixture of stereoisomers thereof and additionallyoptionally as a pharmaceutically acceptable salt thereof. In someembodiments, the disease is selected from glycolipid storage diseases(e.g., Tay Sachs, Sandhoffs, GM1 gangliosidosis—including type, type 2and type 3, Niemanns-Pick, and Fabry diseases); diseases associated withglycolipid accumulation (e.g., Gaucher disease); diseases that causerenal hypertrophy or hyperplasia such as diabetic nephropathy; diseasesthat cause hyperglycemia or hyperinsulemia; cancers in which glycolipidsynthesis is abnormal; infectious diseases caused by organisms which usecell surface glycolipids as receptors or in which synthesis ofglucosylceramide is essential or important; a metabolic disorder such asatherosclerosis, polycystic kidney disease, renal hypertrophy, diabetesmellitus, and obesity; cancer such as breast cancer, renaladenocarcinoma, brain cancer, neuroblastoma, lung cancer, intestinalcancer, pancreas and prostrate cancer; neuronal disorders; neuronalinjury; inflammatory diseases or disorders (e.g., rheumatoid arthritis,Crohn's disease, asthma and sepsis), and diabetes mellitus and obesity.

In another embodiment, the disease is a gangliosidosis with centralnervous system involvement, e.g., Gaucher's type 2, Gaucher's type 3,Gaucher's type 1 in which patients are at a higher risk for peripheralneuropathy and parkinsonian features, Sandhoff, infantile Sandhoff withperipheral neuropathy, GM1 gangliosidosis type 1, GM1 gangliosidosistype 2, GM1 gangliosidosis type, Tay-Sachs, and GM2 gangliosidosis, ABvariant. In another embodiment, the disease is GM1 gangliosidosis type1, GM1 gangliosidosis type 2, GM1 gangliosidosis type, Tay-Sachs, or GM2gangliosidosis with AB variant. In another embodiment, the disease isGaucher's type 2, Gaucher's type 3, Gaucher's type 1 in which patientsare at a higher risk for peripheral neuropathy and parkinsonianfeatures. In another embodiment, the disease is Sandhoff or infantileSandhoff with peripheral neuropathy.

In another embodiment the compounds of Formula I, I(a), I(b), II, II(a),II(b), III, III(a), III(b), IV, IV(a), IV(b), V, V(a), V(b), VI, VI(a),VI(b), VII, VII(a), VII(b), VIII, VIII(a), VIII(b), IX, IX(a), IX(b), X,X(a), X(b), XI, XI(a), XI(b), XII, XII(a), XII(b), XIII, XIII(a),XIII(b), XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, or acompound in Table 1; optionally as a single stereoisomer or mixture ofstereoisomers thereof and additionally optionally as a pharmaceuticallyacceptable salt thereof is one which crosses the blood brain barrier.

Preparation of Compounds

The following are illustrative examples of how the compounds can beprepared and tested. Although the examples can represent only someembodiments, it should be understood that the following examples areillustrative and not limiting.

In a further aspect, it is provided a method of making a compound,comprising synthesizing a compound as any of the various embodimentsdescribed above or below. Examples of the method are further describedin the Examples. All synthetic steps outlined herein may be combinedwith subsequent steps, or may incorporate batches or compounds fromprevious steps.

Compounds disclosed herein are commercially available or can be readilyprepared from commercially available starting materials according toestablished methodology in the art of organic synthesis. General methodsof synthesizing the compound can be found in, e.g., Stuart Warren andPaul Wyatt, Workbook for Organic Synthesis: The Disconnection Approach,second Edition, Wiley, 2010. Synthesis of some of the compounds areexemplified in detail below.

In some embodiments, individual stereoisomers of compounds are preparedsynthetically from commercially available starting materials whichcontain asymmetric or chiral centers or by preparation of racemicmixtures followed by resolution. These methods of resolution areexemplified by (1) attachment of a mixture of enantiomers to a chiralaxillary, separation of the resulting mixture of diastereomers byrecrystallization or chromatography and liberation of the optically pureproduct from the auxiliary or (2) direct separation of the mixture ofoptical enantiomers on chiral chromatographic column.

Materials were obtained from commercial suppliers and were used withoutfurther purification. Air or moisture sensitive reactions were conductedunder argon atmosphere using oven-dried glassware and standardsyringe/septa techniques. ¹H NMR spectra were measured at 400 MHz unlessstated otherwise and data were reported as follows in ppm (δ) from theinternal standard (TMS, 0.0 ppm): chemical shift (multiplicity,integration, coupling constant in Hz).

A Compound of Formula I (where all groups are as defined according toany of the embodiments disclosed herein) can be prepared according toGeneral Scheme 1.

A Compound of Formula I can be prepared using standard amide couplingconditions. More specifically, an intermediate of formula 100, which canbe prepared using procedures disclosed herein or are known to one ofordinary skill in the art, is treated with 101 in a solvent such as DMF,DCM or THF, optionally in the presence of a base such as DIPEA or TEA,and in the presence of a coupling agent such as EDCI and/or HOBt toyield a compound of Formula I. The mixture can optionally be purifiedusing procedures known to one of ordinary skill in the art.Alternatively, the intermediate of formula 101 can be treated with achlorinating agent such as oxalyl chloride in a solvent such as DMFfollowed by treatment with the intermediate of formula 100 to yield acompound of Formula I. The mixture can optionally be purified (orindividual isomers optionally resolved) using procedures known to one ofordinary skill in the art.

SYNTHETIC EXAMPLES Intermediate A

To a solution of Intermediate A1 (20 g, 96 mmol) in1-methyl-2-pyrrolidinone (300 mL) was added cesium carbonate (62.8 g,193 mmol) and bromocyclopropane (24 mL, 289 mmol). The mixture wasstirred for 24 h while keeping internal temperature between 145° C. and155° C. The reaction mixture was cooled to room temperature, dilutedwith water (400 mL), and extracted with a mixture of ethyl acetate inpetroleum ether (15% v/v) (300 mL×3). The combined organic phases werewashed with brine (150 mL×4), dried over anhydrous sodium sulfate,filtered, and concentrated to afford a crude product. The crude productwas purified with flash column chromatography on silica gel (petroleumether) to furnish Intermediate A2. HPLC: Rt: 1.96 minute. ¹H-NMR (CDCl₃,400 MHz): δ (ppm) 0.80-0.88 (m, 4H), 3.67-3.82 (m, 1H), 7.15 (d, J=8.8Hz, 1H), 7.32 (dd, J=8.8, 2.4 Hz, 1H), 7.47 (d, J=2.4 Hz, 1H).

Benzyl chloroformate (50 w.t.% solution in toluene, 50 mL, 148 mmol) wasadded to a solution of (R)-2-amino-3-hydroxypropanoic acid (A3, 10.5 g,100 mmol) in sat. aq NaHCO₃ solution (400 mL). The mixture was stirredvigorously at 20° C. for 4 h. and the aqueous solution was extractedwith ether (400 mL×2). The aqueous phase was acidified with conc.hydrochloric acid to pH=2 and extracted with ethyl acetate (300 mL×3).The combined organic phases were dried with Na₂SO₄ and concentrated toafford Intermediate A4. LC-MS (m/z): 240 [M+1]+; ¹H-NMR (DMSO-d₆, 400MHz) peaks: δ (ppm) 3.653 (m, 2H), 4.051 (m, 1H), 4.884 (m, 1H), 5.038(s, 2H), 7.303-7.373 (m, 6H), 12.658 (s, 1H).

To a mixture of EDCI.HCl (2.4 g, 12.5 mmol), HOBt (1.7 g, 12.5 mmol),DIPEA (2.7 g, 20 mmol) in DCM (50 mL) was added Intermediate A4 (1 g, 4mmol) and N, O-dimethylhydroxylamine hydrochloride (1.2 g, 12.5 mmol)and the reaction mixture was stirred at room temperature overnight. Thereaction mixture was washed with hydrochloric acid solution (1 M, 50mL×2), saturated aqueous NaHCO₃ (20 mL), brine (20 mL), and dried overNa₂SO₄, and concentrated. The crude product was purified by silica gelcolumn chromatography (ethyl acetate in petroleum, 30% v/v) to giveIntermediate A5. LC-MS (m/z): 283 [M+1]; ¹H-NMR (CDCl₃, 400 MHz) peaks:δ (ppm) 3.113 (s, 3H), 3.673 (s, 3H), 3.743 (t, J=4.8 Hz, 2H), 4.766 (m,1H), 4.959-5.044 (m, 2H), 6.046 (d, J=8.0 Hz, 1H), 7.200-7.254 (m 5H).

To a solution of Intermediate A5 (500 mg, 1.77 mmol) and imidazole (602mg, 8.86 mmol) in THF (20 mL) at 0° C. was added dropwise a solution ofTBDMS-Cl (800 mg, 5.31 mmol) in THF (10 mL) and the reaction mixture wasstirred at room temperature for 2 h. The reaction mixture was filtered,washed with IN HCl (50 mL×2) and brine (50 mL), and dried over Na₂SO₄,and concentrated. The crude product was purified with silica gel columnchromatography (ethyl acetate in petroleum, 13% v/v) to giveIntermediate A6. LC-MS (m/z): 396 [M+1]; ¹H-NMR (CDCl₃, 400 MHz) peaks:δ (ppm) 0.012 (s, 3H), 0.085 (s, 6H), 0.852 (s, 9H), 3.211 (s, 3H),3.756 (s, 3H), 3.794-3.896 (m, 2H), 4.809 (m, 1H), 5.085 (q, J=11.2 Hz,2H), 5.662 (d, J=8.8 Hz, 1H), 7.286-7.351 (m 5H).

To a solution of Intermediate A2 (70 g, 283 mmol) in dry THF (700 mL) at−70° C. under nitrogen atmosphere was added dropwise n-BuLi (2.4 M inhexane, 118 mL) over a period of 20 minutes. After the mixture wasstirred at −70° C. for 40 minutes, to the mixture was slowly added asolution of Intermediate A6 (44.8 g, 113 mmol) in dry THF (50 mL) at arate that maintained the internal temperature between −70° C. and −50°C. The mixture was stirred for 1 h. The reaction mixture was quenchedwith saturated ammonium chloride solution (400 mL) and extracted withethyl acetate (300 mL×3). The organic phase was washed with water (200mL) and brine (200 mL), dried over anhydrous sodium sulfate, filtered,and concentrated to furnish a crude product. The crude product waspurified with flash column chromatography on silica gel (ethyl acetatein petroleum ether, from 5% to 10% v/v) to furnish Intermediate A7.LC-MS (ESI) m/z: 504 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 0.01 (d,J=6.0 Hz, 6H), 0.87 (s, 9H), 1.02 (d, J=4.8 Hz, 4H), 1.36-1.40 (m, 1H),3.99-4.03 (m, 1H), 4.09 (dd, J=10.0, 3.6 Hz, 1H), 5.26 (s, 2H),5.42-5.44 (m, 1H), 6.04 (d, J=8.0 Hz, 1H), 7.44-7.50 (m, 6H), 8.00 (dd,J=8.8, 1.6 Hz, 1H), 8.11 (s, 1H).

A solution of Intermediate A7 (6.0 g, 11.9 mmol) in a mixture of THF,water, and glacial acetic acid (125 mL, 1/1/3, v/v/v) was stirred at 25°C. for 30 h. The reaction mixture was concentrated under reducedpressure to remove excess solvent. The residue was poured into ice water(20 g) and its pH was adjusted to 7-8 with aqueous sodium hydroxide (1N) and saturated aqueous sodium bicarbonate. The mixture was extractedwith ethyl acetate (60 mL×3). The combined organic phases were washedwith brine (50 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated to afford a crude product, which was further purified withflash column chromatography on silica gel (ethyl acetate in petroleumether, from 30% to 50% v/v) to give Intermediate A8. LC-MS (ESI) m/z:390 [M+H]⁺, 412 [M+Na]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 0.89 (d, J=4.5Hz, 4H), 2.78 (s, 1H), 3.81-3.92 (m, 2H), 4.01 (d, J=9.4 Hz, 1H),5.08-5.17 (m, 2H), 5.26-5.38 (m, 1H), 6.12 (d, J=6.9 Hz, 1H), 7.25-7.45(m, 6H), 7.92 (d, J=8.5 Hz, 1H), 8.02 (s, 1H).

To a solution of Intermediate A8 (3.3 g, 7.7 mmol) in dry THF (140 mL)under nitrogen atmosphere at −78° C. was added dropwise a solution ofdiisobutylaluminum hydride (1.0 M in toluene, 31 mL) over a period of 15minutes. After the reaction was stirred at −70° C. for 1 h, a solutionof HCl (2 N, 40 mL) was slowly added. The reaction mixture was extractedwith ethyl acetate (30 mL×3), dried over anhydrous sodium sulfate,filtered, and concentrated to afford a crude product, which was furtherpurified with flash column chromatography on silica gel (ethyl acetatein petroleum ether, from 50% to 150% v/v) to furnish Intermediate A9.LC-MS (ESI) m/z: 374 [M-OH]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 0.80-0.83(m, 4H), 1.23-1.27 (m, 1H), 2.79 (s, 1H), 3.45 (d, J=2.0 Hz, 1H),3.74-3.81 (m, 4H), 4.93-5.08 (m, 2H), 5.52-5.54 (m, 1H), 7.16-7.37 (m,8H).

To a solution of Intermediate A9 (900 mg, 2.30 mmol) in THF (20 mL) wasadded triethylamine (698 mg, 6.89 mmol). To the mixture at −30° C. wasadded dropwise methanesulfonyl chloride (290 mg, 2.53 mmol) over aperiod of 15 minutes. The reaction mixture was stirred at −30° C. for1.5 h, diluted with water (50 mL), and extracted with ethyl acetate (50mL×2). The combined organic layers were washed with brine (50 mL), driedover anhydrous sodium sulfate, filtered, and concentrated to affordIntermediate A10, which was directly used for the next step withoutfurther purification. LC-MS (ESI) m/z: 452 [M-OH]⁺.

To a solution of Intermediate A10 (1.12 g, 2.83 mmol) in THF (60 mL) wasadded pyrrolidine (2 g, 28 mmol) and the reaction mixture was heated at50° C. for 16 h. The reaction mixture was diluted with water (30 mL),extracted with ethyl acetate (150 mL×2), washed with brine (50 mL),dried over anhydrous sodium sulfate, filtered, and concentrated. Thecrude product was purified with flash column chromatography on silicagel (methanol in dichloromethane, 5% v/v) to give Intermediate A11.LC-MS (ESI) m/z: 445 [M+H]⁺.

To a solution of Intermediate A11 (520 mg, 1.17 mmol) in ethanol (12 mL)and water (2 mL) was added LiOH*H₂O (197 mg, 4.68 mmol) and the reactionmixture was heated at 80° C. for 16 h. The reaction mixture was dilutedwith water (15 mL) and extracted with dichloromethane (50 mL×2). Thecombined organic phases were washed with water (50 mL) and brine (50mL), dried over anhydrous sodium sulfate, filtered, and concentrated tofurnish Intermediate A, which was directly used for the next stepwithout further purification. LC-MS (ESI) m/z: 311 [M+H]⁺.

Intermediate B

Intermediates B1 and B were synthesized by employing the proceduresdescribed for Intermediates A11 and A using azetidine and IntermediatesB1 in lieu of pyrrolidine and Intermediate A11.

Intermediate B1. LC-MS (ESI) m/z: 431 [M+H]⁺.

Intermediate B, which was directly used for the next step withoutfurther purification. LC-MS (ESI) m/z: 297 [M+H]⁺.

Intermediate C

To a solution of Intermediate C1 (50 g, 357 mmol) in MeCN (400 mL) wasadded NBS (60.08 g, 360 mmol) and HCOONH₄ (2.47 mg, 39 mmol) at roomtemperature and the reaction mixture was stirred at room temperature for2 h. After removal of the solvent, the mixture was diluted with ethylacetate (200 mL), washed with brine, dried over anhydrous Na₂SO₄, andconcentrated to give Intermediate C2. ¹H-NMR (CDCl₃, 400 MHz): δ (ppm)7.48-7.23 (m, 2H), 9.87 (s, 1H), 10.89 (s, 1H).

To a solution of Intermediate C2 (40 g, 183 mmol) in THF (260 mL) at 0°C. was added dropwise aq. NaOH solution (0.05 N, 720 mL, 37 mmol),followed by 30% H₂O₂ solution (90 mL). The mixture was stirred at roomtemperature 2 h., followed by addition of a second portion of 30% H₂O₂(90 mnL). After stirring for 4 h, it was cooled to 0° C. and aq. NaOHsolution (2 N, 112 mL) was added until pH 10-11. The mixture was stirredfor 0.5 h., quenched with conc. HCl at 0° C. to pH 2-3, extracted withdichloromethane (250 mL×3), washed with brine (300 mL×2), dried overNa₂SO₄, and concentrated to give Intermediate C3. LC-MS (m/z): 205[M-1]⁻.

To a mixture of Intermediate C3 (30 g, 146 mol) and K₂CO₃ (60.3 g, 437mol) in DMF (450 mL) was added 1, 2-dibromoethane (63 mL, 730 mol) andthe reaction mixture was stirred at 80° C. for 4 h. After the reactionmixture was cooled to room temperature, it was filtered and the cake waswashed with EtOAc (100 mL). The filtrate was diluted with water (900 mL)and extracted with EtOAc (400 mL×3). The organic layer was washed withwater (900 mL×5) and brine (900 ml×1), dried, concentrated, and purifiedby column chromatography on silica gel (ethyl acetate in petroleum, 5%v/v) to afford Intermediate C4. ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 4.35(s, 4H), 6.91 (t, J=8 Hz, 1H), 7.33 (s, 1H).

Intermediates C5, C6, C7, C8, and C9 were synthesized by employing theprocedures described correspondingly for Intermediates A7, A8, A9, A10,and A11 using Intermediates C4, C5, C6, C7, and C8 in lieu ofIntermediates A2, A7, A8, A9, and A10.

Intermediate C5. LC-MS (m/z): 490 [M+1]⁺.

Intermediate C6. LC-MS (ESI) m/z: 376 [M+H]⁺; 1H-NMR (CDCl₃, 400 MHz): δ(ppm) 2.50-2.53 (m, 1H), 3.78-3.83 (m, 1H), 3.91-3.97 (m, 1H), 4.25-4.27(m, 2H), 4.31-4.33 (m, 2H), 5.07 (s, 2H), 6.00 (d, J=4 Hz, 1H),7.24-7.31 (m, 7H).

Intermediate C7. LC-MS (ESI) m/z: 360 [M-OH]⁺; ¹H-NMR (CDCl₃, 400 MHz):δ (ppm) 3.45-3.59 (m, 3H), 4.23-4.24 (m, 4H), 4.84 (s, 1H), 5.00 (s,2H), 5.54 (d, J=8 Hz, 1H), 6.69 (t, J=8 Hz, 2H), 7.27-7.35 (m, 5H).

Intermediate C8. LC-MS (m/z): 438 [M+1-18].

Intermediate C9. LC-MS (m/z): 431 [M+l]⁺.

To a solution of Intermediate C9 (2.15 g, 5 mmol) in ethanol (60 mL) wasadded 10% Pd(OH)₂ (200 mg). The solution was stirred under H₂ atmosphereat 25° C. for 24 h, filtered, and concentrated to yield Intermediate C,which was directly used for the next step. LC-MS (ESI) m/z: 297 [M+H]⁺;¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 1.75-1.79 (m, 4H), 2.46-2.89 (m, 6H),3.06-3.10 (m, 1H), 4.28 (s, 4H), 4.50 (d, J=4 Hz, 1H), 6.65-6.77 (m,2H).

Intermediate D

Intermediates D2, D3, D4, D5, D6, and D7 were synthesized by employingthe procedures described for Intermediates A2, A7, A5, A9, A10, and A11using Intermediates D1, D2, D3, D4, D5, and D6 in lieu of IntermediatesA1, A2, A7, A8, A9, and A10.

Intermediate D2. ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 0.79-0.84 (m, 4H),3.78-3.80 (m, 1H), 7.14-7.23 (m, 3H).

Intermediate D3. LC-MS (ESI) m/z: 488 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz):δ (ppm) −0.08 (s, 6H), 0.82 (m, 11H), 0.84-0.88 (m, 2H), 3.81-3.90 (m,2H), 4.05-4.09 (m, 1H), 5.03 (s, 2H), 5.13-5.18 (m, 1H), 7.27-7.36 (i,5H), 7.53 (t, J=8.4 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.74 (dd, J=12.0,2.4 Hz, 1H), 7.86 (d, J=8.4 Hz, 1H).

Intermediate D4. LC-MS (ESI) m/z: 374 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz):δ (ppm) 0.75-0.89 (m, 4H), 3.62-3.78 (m, 2H), 4.07-4.09 (m, 1H), 4.91(t, J=5.6 Hz, 1H), 5.03 (s, 2H), 5.10-5.14 (m, 1H), 7.26-7.38 (m, 5H),7.55 (t, J=8.8 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.79 (dd, J=12.0, 1.6Hz, 1H), 7.90 (d, J=8.4 Hz, 1H).

Intermediate D5. LC-MS (ESI) m/z: 376 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz):δ (ppm) 0.38-0.81 (m, 4H), 3.25-3.31 (m, 1H), 3.47-3.53 (m, 1H),3.64-3.65 (m, 1H), 3.88-3.91 (m, 1H), 4.72-4.77 (m, 2H), 4.87-5.01 (m,2H), 5.37 (d, J=5.2 Hz, 1H), 6.75 (d, J=10.0 Hz, 1H), 7.05-7.34 (m, 8H).

Intermediate D6, which was used for the next step without furtherpurification. LC-MS (ESI) m/z: 436 [M-OH]⁺.

Intermediate D7. LC-MS (ESI) m/z: 429 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz):δ (ppm) 0.68-0.81 (m, 4H), 1.66 (s, 4H), 2.24-2.50 (m, 5H), 2.59-2.64(m, 1H), 3.75-3.81 (m, 1H), 3.88-3.91 (m, 1H), 4.72 (s, 1H), 4.87-5.00(m, 2H), 5.52 (brs, 1H), 6.79 (d, J=9.2 Hz, 1H), 7.05-7.13 (m, 2H),7.17-7.34 (m, 6H).

Intermediate D was synthesized by employing the procedure described forIntermediate C using Intermediate D7 in lieu of Intermediate C9. LC-MS(ESI) m/z: 295 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 0.67-0.79 (m,4H), 1.23 (s, 2H), 1.65 (s, 4H), 2.16-2.20 (m, 1H), 2.29-2.36 (m, 6H),2.86-2.89 (m, 1H), 3.89-3.93 (m, 1H), 4.38 (d, J=4.8 Hz, 1H), 7.06-7.15(m, 2H), 7.32 (t, J=8.4 Hz, 1H).

Intermediate E

Intermediate E1 was synthesized by employing the procedure described forIntermediate A11 using azetidine and Intermediate D6 in lieu ofpyrrolidine and Intermediate A10. LC-MS (ESI) m/z: 415 [M+H]⁺; ¹H-NMR(DMSO-d₆, 400 MHz): δ (ppm) 0.65-0.83 (m, 4H), 1.91-1.99 (m, 2H),2.27-2.32 (m, 1H), 3.12-3.17 (m, 5H), 3.48-3.57 (m, 1H), 3.87-3.91 (m,1H), 4.65 (d, J=3.2 Hz, 1H), 4.87-5.00 (m, 2H), 6.78 (d, J=9.6 Hz, 1H),7.03 (d, J=8.4 Hz, 1H), 7.07-7.34 (m, 7H).

Intermediate E was synthesized by employing the procedure described forIntermediate C using Intermediate E1 in lieu of Intermediate C9. LC-MS(ESI) m/z: 281 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 0.67-0.81 (m,4H), 1.89-1.96 (m, 2H), 2.15-2.26 (m, 2H), 2.61-2.65 (m, 1H), 3.03-3.13(m, 4H), 3.87-3.93 (m, 1H), 4.34 (d, J=4.8 Hz, 1H), 7.01-7.12 (m, 2H),7.26-7.34 (m, 1H).

Intermediate F

Intermediates F2, F3, F4, F5, F6, F7, and F, were synthesized byemploying the procedures described for Intermediates A2, A7, A8, A9,A10, A11, and A using Intermediates F1, F2, F3, F4, F5, F6, and F7, inlieu of Intermediates A1, A2, A7, A8, A9, A10, and A11.

Intermediate F2. LC-MS (ESI) m/z: retention time: 2.19 minute; ¹H-NMR(CDCl₃, 400 MHz): δ (ppm) 0.66-0.75 (m, 4H), 3.60-3.71 (m, 1H),6.82-7.02 (m, 2H), 7.28-7.41 (m, 2H).

Intermediate F3. LC-MS (ESI) m/z: 470 [M+H]⁺.

Intermediate F4. LC-MS (ESI) m/z: 356 [M+H]⁺, 378 [M+Na]⁺; ¹H NMR(DMSO-d₆, 400 MHz): δ (ppm) 0.65-0.72 (m, 2H), 0.78-0.88 (m, 2H),3.58-3.71 (m, 1H), 3.75-3.80 (m, 1H), 3.94-3.99 (m, 1H), 4.89 (t, J=5.8Hz, 1H), 5.04 (s, 2H), 5.16 (dd, J=13.0, 5.5 Hz, 1H), 7.17 (d, J=8.7 Hz,2H), 7.32-7.38 (m, 4H), 7.51 (d, J=7.9 Hz, 1H), 8.00 (d, J=8.7 Hz, 2H).

Intermediate F5. LC-MS (ESI) m/z: 340 [M-OH]⁺. ¹H-NMR (CDCl₃, 400 MHz):δ (ppm) 0.74-0.77 (m, 4H), 1.81 (s, 1H), 2.76 (s, 1H), 3.23 (s, 1H),3.65-3.90 (m, 4H), 4.92-5.08 (m, 2H), 5.51 (d, J=7.8 Hz, 1H), 6.99 (d,J=8.6 Hz, 2H), 7.27-7.38 (m, 7H).

Intermediate F6. LC-MS (ESI) m/z: 418 [M-OH]⁺, 458 [M+Na]⁺. H-NMR(CDCl₃, 400 MHz): δ (ppm) 0.66-0.84 (m, 4H), 1.76 (s, 1H), 2.92-2.96 (m,3H), 3.69-3.74 (m, 1H), 4.07-4.17 (m, 2H), 4.34-4.39 (m, 1H), 4.89 (s,1H), 5.00-5.03 (m, 2H), 5.40 (d, J=7.1 Hz, 1H), 7.00 (d, J=8.6 Hz, 2H),7.16-7.75 (m, 7H).

Intermediate F7. LC-MS (ESI) m/z: 411 [M+H]⁺.

Intermediate F, which was directly used for the next step withoutfurther purification. LC-MS (ESI) m/z: 277 [M+H]; ¹H-NMR (DMSO-d₆, 400MHz): δ (ppm) 0.60-0.64 (m, 2H), 0.74-0.78 (m, 2H), 1.23 (s, 1H), 1.65(s, 4H), 2.10-2.14 (m, 1H), 2.28-2.49 (m, 6H), 2.87-2.90 (m, 1H),3.77-3.82 (m, 1H), 4.33 (d, J=5.0 Hz, 1H), 6.98 (d, J=8.4 Hz, 2H), 7.22(d, J=8.8 Hz, 2H).

Intermediate G

Intermediate G1 and G were synthesized by employing the proceduresdescribed for Intermediate A11 and A using azetidine and Intermediate F6in lieu of pyrrolidine and Intermediate A10.

Intermediate G1. LC-MS (ESI) m/z: 397 [M+H]⁺.

Intermediate G, which was directly used for the next step withoutfurther purification. LC-MS (ESI) m/z: 263 [M+H]⁺.

Intermediate H

To a solution of Intermediate A11 (111 mg, 0.25 mmol) in THF (15 mL)under nitrogen was added LiAlH₄ (38 mg, 1 mmol). The resulting mixturewas stirred at 60° C. for 3 h., quenched with NH₃. H₂O (3 mL), andfiltered. The filtrate was treated with water (20 mL) and extracted withethyl acetate (20 mL×2). The combined organic layers were washed withbrine (40 mL), dried over anhydrous sodium sulfate, and concentrated toafford a crude product. It was purified with prep-HPLC to giveIntermediate H, which was used without further purification. LC-MS (ESI)m/z: 325 [M+H]⁺.

Intermediate I

Intermediate I was synthesized by employing the procedure described forIntermediate H using Intermediate D7 in lieu of Intermediate A11, whichwas used without further purification. LC-MS (ESI) m/z: 309 [M+H]⁺;¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 0.75-0.85 (m, 4H), 1.76-1.79 (m, 4H),2.34 (s, 3H), 2.43-2.59 (m, 6H), 2.87-2.91 (m, 1H), 3.77-3.82 (m, 1H),4.63-4.69 (m, 1H), 7.02-7.12 (m, 2H), 7.22-7.26 (m, 1H).

Intermediate J

Intermediate J was synthesized by employing the procedure described forIntermediate H using Intermediate B1 in lieu of Intermediate A11, whichwas used without further purification. LC-MS (ESI) m/z: 311 [M+H]⁺.

Example 1

To a solution of Compound 1A (1.7 g, 10 mmol) in 1,4-dioxane (60 mL) andwater (10 mL) was added 4-fluorophenylboronic acid (1.4 g, 10 mmol),K₂CO₃ (4.14 g, 30 mmol), and Pd(dppf)Cl₂ (366 mg, 0.5 mmol). The mixturewas stirred under nitrogen at 90° C. overnight. The resulting solutionwas cooled down to room temperature and filtered on Celite. Afterremoval of the solvent, the residue was diluted with water (950 mL) andextracted with ethyl acetate (100 mL×3). The organic layer was washedwith water (10 mL) and brine (10 mL), dried over anhydrous sodiumsulfate, filtered, and concentrated to yield a crude product. The crudeproduct was purified with flash column chromatography on silica gel(ethyl acetate in petroleum ether, 10% v/v) to furnish Compound B.¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 2.42 (s, 3H), 7.12 (t, J=8.8 Hz, 2H),7.14-7.17 (i, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.35 (d, J=8.8 Hz, 2H),7.52-7.55 (i, 2H).

To a suspension of AlCl₃ (1.74 g, 13 mmol) in dry dichioromethane (100mL) was added Compound 1B (1.86 g, 10 mmol) and ethyl2-chloro-2-oxoacetate (1.17 mL, 10.5 mmol) at 0° C. The mixture waswarmed to room temperature and stirred for 16 h. The resulting mixturewas quenched with saturated ammonium chloride solution (20 mL) andextracted with dichloromethane (50 mL×3). The organic layer was washedwith water (10 mL) and brine (10 mL), dried over anhydrous sodiumsulfate, filtered, and concentrated to yield a crude product. The crudeproduct was purified with flash column chromatography on silica gel(ethyl acetate in petroleum ether, 10% v/v) to afford Compound 1C. LC-MS(ESI) m/z: 287 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 1.44 (t, J=6.8Hz, 3H), 4.46 (q, J=7.2 Hz, 2H), 7.17 (t, J=8.4 Hz, 2H), 7.49-7.50 (m,2H), 7.58-7.62 (m, 2H), 7.78 (d, J=8.8 Hz, 1H), 2.69 (s, 3H).

To a solution of Compound 1C (545 mg, 1.91 mmol) in CCl₄ (20 mL) wasadded NBS (373 mg, 2.1 mmol) and BPO (46 mg, 0.19 mmol). The mixture washeated to reflux for 3 h. The resulting mixture was cooling down to roomtemperature and extracted with dichloromethane (50 mL×3). The organiclayer was washed with water (10 mL) and brine (10 mL), dried overanhydrous sodium sulfate, filtered, and concentrated to yield a crudeproduct. The crude product was purified with flash column chromatographyon silica gel (ethyl acetate in petroleum ether, 10% v/v) to furnishCompound 1D. LC-MS (ESI) m/z: 365 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ(ppm) 1.44 (t, J=7.2 Hz, 3H), 4.47 (q, J=7.2 Hz, 2H), 4.88 (s, 2H), 7.19(t, J=8.8 Hz, 2H), 7.60-7.63 (m, 3H), 7.73-7.74 (m, 1H), 7.84 (d, J=8.4Hz, 1H).

To a solution of 2-hydroxyisoindoline-1,3-dione (1.54 g, 9.43 mmol) inDMF/acetonitrile/water (44 mL, 5/1/5 v/v) was added Na₂CO₃ (2.50 g, 23.6mmol). After stirring for 2 h, Compound 1D (3.64 g, 10 mmol) was addedto the above mixture and the resulting mixture was stirred at roomtemperature overnight. After filtration, the cake was washed with water(5 mL×3) and dried to furnish Compound 1E. LC-MS (ESI) m/z: 448 [M+H]⁺;¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 1.43 (t, J=7.2 Hz, 3H), 4.46 (q, J=7.2Hz, 2H), 5.72 (s, 2H), 7.19 (t, J=8.4 Hz, 2H), 7.66 (dd, J=8.0, 1.6 Hz,1H), 7.68-7.72 (m, 2H), 7.76 (d, J=8.0 Hz, 1H), 7.77 (d, J=6.0 Hz, 1H),7.85-7.87 (m, 2H), 7.89 (d, J=8.4 Hz, 1H), 8.26 (s, 1H).

To a solution of Compound 1E (556 mg, 1.24 mmol) in ethanol (30 mL) wasadded 80% hydrazine hydrate (7 drops, 3.72 mmol). The mixture wasstirred at room temperature for 1 h. The resulting mixture was adjustedto pH 7 with aqueous HCl solution (2 N, 0.5 mL) and evaporated. Theresidue was diluted with water (30 mL) and extracted with ethyl acetate(50 mL×3). The organic layer was washed with water (10 mL) and brine (10mL), dried over anhydrous sodium sulfate, filtered, and concentrated toyield a crude product. The crude product was purified with flash columnchromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v)to afford Compound 1F. LC-MS (ESI) m/z: 300 [M+H]; ¹H-NMR (CDCl₃, 400MHz): δ (ppm) 1.46 (t, J=7.2 Hz, 3H), 4.48 (q, J=7.2 Hz, 2H), 5.11 (s,2H), 7.17 (t, J=8.8 Hz, 2H), 7.34 (s, 1H), 7.56-7.60 (m, 2H), 7.62 (d,J=1.6 Hz, 1H), 8.01 (d, J=8.4 Hz, 1H).

To a solution of Compound 1F (322 mg, 1.08 mmol) in THF (12 mL) wasadded dropwise a solution of LiOH.H₂O (181 mg, 4.31 mmol) in water (3mL). The mixture was stirred at room temperature for 1 h. The reactionsolution was adjusted to pH 4 with aqueous HCl solution (1 N, 1.5 mL)and separated. The organic layer was dried directly over anhydroussodium sulfate, filtered, and concentrated to afford Compound 1G. LC-MS(ESI) m/z: 233 [M−H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 5.12 (s, 2H),7.35 (t, J=8.8 Hz, 2H), 7.63 (d, J=1.6 Hz, 1H), 7.77-7.81 (m, 2H), 7.87(d, J=8.0 Hz, 2H).

To a solution of Intermediate A (109 mg, 0.35 mmol) in dichloromethane(10 mL) under nitrogen was added Compound 1G (80 mg, 0.30 mmol), EDCI(85 mg, 0.44 mmol), HOBt (60 mg, 0.44 mmol), and DIPEA (114 mg, 0.88mmol). The mixture was stirred at room temperature overnight. Theresulting mixture was diluted with saturated aqueous sodium bicarbonatesolution (50 mL) and extracted with dichloromethane (50 mL×3). Thecombined organic phases were washed with water (50 mL) and brine (50mL), dried over anhydrous sodium sulfate, filtered, and concentrated toafford a crude product. The crude product was purified with prep-HPLC tofurnish Compound 1. LC-MS (ESI) m/z: 564 [M+H]⁺; ¹H-NMR (CD₃OD, 400MHz): δ (ppm) 0.69-0.80 (i, 4H), 2.05-2.07 (m, 2H), 2.19-2.22 (m, 2H),3.21-3.28 (m, 2H), 3.53-3.57 (m, 1H), 3.70-3.83 (m, 4H), 4.69-4.71 (m,1H), 4.95 (d, J=2.8 Hz, 1H), 5.11 (d, J=3.6 Hz, 2H), 7.23 (t, J=8.8 Hz,2H), 7.35-7.39 (m, 3H), 7.48 (s, 1H), 7.53 (s, 1H), 7.56 (d, J=8.0 Hz,1H), 7.69-7.73 (m, 2H).

Example 2

Compound 2 was synthesized by employing the procedure described forCompound 1 using Intermediate D in lieu of Intermediate A. LC-MS (ESI)m/z: 548 [M+H]⁺; H-NMR (CD₃OD, 400 MHz): δ (ppm) 0.69-0.78 (m, 4H),2.05-2.06 (m, 2H), 2.20-2.22 (m, 2H), 3.20-3.27 (m, 2H), 3.52-3.56 (m,1H), 3.68-3.74 (m, 2H), 3.81-3.85 (m, 2H), 4.69-4.72 (m, 1H), 4.94 (d,J=2.8 Hz, 1H), 5.11 (d, J=4.0 Hz, 2H), 7.20-7.25 (m, 4H), 7.33 (t, J=8.4Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.53 (s, 1H), 7.58 (d, J=8.4 Hz, 1H),7.69-7.72 (m, 2H).

Example 3

Compound 3 was synthesized by employing the procedure described forCompound 1 using Intermediate C in lieu of Intermediate A. LC-MS (ESI)m/z: 550 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ (ppm) 2.04-2.05 (m, 2H),2.19-2.21 (m, 2H), 3.19-3.29 (m, 2H), 3.50-3.54 (m, 1H), 3.67-3.73 (m,2H), 3.79-3.81 (m, 1H), 4.16-4.24 (m, 4H), 4.65-4.68 (m, 1H), 4.86 (d,J=2.4 Hz, 1H), 5.11 (d, J=3.6 Hz, 2H), 6.80-6.83 (m, 2H), 7.22 (t, J=8.0Hz, 2H), 7.53-7.58 (m, 2H), 7.61-7.63 (m, 1H), 7.69-7.73 (m, 2H).

Example 4

Compound 4 was synthesized by employing the procedure described forCompound 1 using Intermediate F in lieu of Intermediate A. LC-MS (ESI)m/z: 530 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ (ppm) 0.64-0.76 (m, 4H),2.04-2.06 (m, 2H), 2.17-2.21 (m, 2H), 3.21-3.28 (m, 2H), 3.51-3.55 (m,1H), 3.66-3.75 (m, 3H), 3.80-3.84 (m, 1H), 4.68-4.71 (m, 1H), 4.95 (d,J=3.2 Hz, 1H), 5.06-5.16 (m, 2H), 7.02 (d, J=8.4 Hz, 2H), 7.23 (t, J=8.4Hz, 2H), 7.38 (d, J=8.4 Hz, 2H), 7.48 (d, J=8.4 Hz, 1H), 7.53 (s, 1H),7.56 (dd, J=8.0, 1.6 Hz, 1H), 7.67-7.72 (m, 2H).

Example 5

Compound 5 was synthesized by employing the procedure described forCompound 1 using Intermediate B in lieu of Intermediate A. LC-MS (ESI)m/z: 550 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ (ppm) 0.69-0.80 (m, 4H),2.44-2.48 (m, 1H), 2.60-2.67 (m, 1H), 3.60-3.62 (m, 2H), 3.81-3.85 (m,1H), 4.24-4.34 (m, 4H), 4.51-4.55 (m, 1H), 4.93 (d, J=2.8 Hz, 1H),5.07-5.15 (m, 2H), 7.23 (t, J=8.8 Hz, 2H), 7.35-7.38 (m, 3H), 7.47 (s,1H), 7.53 (s, 1H), 7.56 (dd, J=8.0, 1.6 Hz, 1H), 7.69-7.73 (m, 2H).

Example 6

Compound 6 was synthesized by employing the procedure described forCompound 1 using Intermediate G in lieu of Intermediate A. LC-MS (ESI)m/z: 516 [M+H]⁺; H-NMR (CD₃OD, 400 MHz): δ (ppm) 0.64-0.76 (m, 4H),2.43-2.45 (m, 1H), 2.59-2.66 (m, 1H), 3.53-3.63 (m, 2H), 3.71-3.76 (m,1H), 4.22-4.31 (m, 4H), 4.51-4.54 (m, 1H), 4.92 (d, J=3.2 Hz, 1H),5.05-5.15 (m, 2H), 7.03 (d, J=8.8 Hz, 2H), 7.22 (t, J=8.8 Hz, 2H), 7.37(d, J=8.8 Hz, 2H), 7.48 (d, J=8.8 Hz, 1H), 7.52 (s, 1H), 7.58 (d, J=8.4Hz, 1H), 7.68-7.72 (m, 2H).

Example 7

Compound 7 was synthesized by employing the procedure described forCompound 1 using Intermediate E in lieu of Intermediate A. LC-MS (ESI)m/z: 534 [M+H]⁺; H-NMR (CD₃OD, 400 MHz): δ (ppm) 0.70-0.78 (m, 4H),2.43-2.48 (m, 1H), 2.60-2.67 (m, 1H), 3.58-3.61 (m, 2H), 3.82-3.86 (m,1H), 4.23-4.33 (m, 4H), 4.51-4.55 (m, 1H), 4.92 (d, J=2.4 Hz, 1H),5.07-5.14 (m, 2H), 7.19-7.25 (m, 4H), 7.34 (t, J=8.8 Hz, 1H), 7.46 (d,J=8.0 Hz, 1H), 7.53 (s, 1H), 7.58 (dd, J=8.0, 1.2 Hz, 1H), 7.69-7.72 (m,2H).

Example 8

Compounds 8B, 8C, 8D, and 8E were synthesized by employing the proceduredescribed for Compounds 1C, 1D, 1E, and 1F using Compounds 8A, 8B, 8C,and 8D in lieu of Compounds 1B, 1C, 1D, and 1E.

Compound 8B. LC-MS (ESI) m/z: 271 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ(ppm) 1.42 (t, J=8.0 Hz, 3H), 2.58 (s, 3H), 4.40-4.46 (q, J=8.0 Hz, 2H),7.45-7.49 (m, 2H), 7.57 (d, J=8.0 Hz, 1H).

Compound 8C. LC-MS (ESI) m/z: 349 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ(ppm) 1.42 (t, J=8.0 Hz, 3H), 4.41-4.47 (q, J=8.0 Hz, 2H), 4.83 (s, 2H),7.57-7.62 (m, 2H), 7.72-7.73 (m, 1H).

Compound 8D. LC-MS (ESI) m/z: 432 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ(ppm) 1.28 (t, J=6.8 Hz, 3H), 4.31-4.37 (q, J=6.8 Hz, 2H), 5.49 (s, 2H),7.82-7.85 (m, 6H), 8.16 (s, 1H).

Compound 8D. LC-MS: (ESI) m/z: 284 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ(ppm) 1.43 (t, J=6.8 Hz, 3H), 4.42-4.48 (q, J=6.8 Hz, 2H), 5.01 (s, 2H),7.34 (d, J=1.6 Hz, 1H), 7.56-7.60 (m, 1H), 7.85 (d, J=8.8 Hz, 1H).

Compound 8F was synthesized by employing the procedure described forCompound 1B using 5-chlorothiophen-2-ylboronic acid and Na₂CO₃ in lieuof 4-fluorophenylboronic acid and K₂CO₃. LC-MS (ESI) m/z: 294 [M−H]⁺;¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 4.83 (s, 2H), 7.20 (d, J=4.0 Hz, 1H),7.49-7.51 (m, 2H), 7.63 (d, J=8.0 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H).

To a solution of Intermediate D (55 mg, 0.19 mmol) in DMF (3 mL) andtriethylamine (0.2 mL) was added Compound 8F (60 mg, 0.19 mmol) and HATU(106 mg, 0.28 mmol). The mixture was stirred at room temperatureovernight. The resulting mixture was purified with prep-HPLC to furnishCompound 8. LC-MS (ESI) m/z: 570 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ(ppm) 0.68-0.82 (m, 4H), 2.01-2.23 (m, 4H), 3.18-3.32 (m, 2H), 3.52-3.56(m, 1H), 3.68-3.86 (m, 4H), 4.66-4.71 (m, 1H), 4.94 (d, J=2.4 Hz, 1H),5.07 (d, J=4.0 Hz, 2H), 7.04 (d, J=4.0 Hz, 1H), 7.19-7.22 (m, 2H),7.30-7.43 (m, 3H), 7.51-7.54 (m, 2H).

Example 9

Compound 9 was synthesized by employing the procedure described forCompound 8 using Intermediate E in lieu of Intermediate D. LC-MS (ESI)m/z: 556 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ (ppm) 0.67-0.80 (m, 4H),2.41-2.49 (m, 1H), 2.58-2.67 (m, 1H), 3.54-3.65 (m, 2H), 3.81-3.87 (m,1H), 4.22-4.36 (m, 4H), 4.49-4.54 (m, 1H), 4.92 (d, J=2.4 Hz, 1H), 5.07(d, J=4.0 Hz, 2H), 7.04 (d, J=4.0 Hz, 1H), 7.18-7.21 (m, 2H), 7.30-7.43(m, 3H), 7.51-7.54 (m, 2H).

Example 10

Compound 10 was synthesized by employing the procedure described forCompound 8 using Intermediate A in lieu of Intermediate D. LC-MS (ESI)m/z: 586 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ (ppm) 0.67-0.85 (m, 4H),1.99-2.24 (m, 4H), 3.18-3.32 (m, 2H), 3.53-3.85 (m, 5H), 4.66-4.71 (m,1H), 4.95 (d, J=2.4 Hz, 1H), 5.03-5.12 (m, 2H), 7.04 (d, J=4.4 Hz, 1H),7.30-7.37 (m, 4H), 7.46-7.51 (m, 3H).

Example 11

Compound 11 was synthesized by employing the procedure described forCompound 8 using Intermediate G in lieu of Intermediate D. LC-MS (ESI)m/z: 538 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ (ppm) 0.62-0.78 (m, 4H),2.41-2.65 (m, 2H), 3.52-3.63 (m, 2H), 3.71-3.76 (m, 1H), 4.16-4.34 (m,4H), 4.48-4.53 (m, 1H), 4.93 (d, J=3.2 Hz, 1H), 5.00-5.12 (m, 2H),7.00-7.04 (m, 3H), 7.34-7.37 (m, 4H), 7.49-7.52 (m, 2H).

Example 12

To a solution of Compound 12A (5.0 g, 27.37 mmol) in THF (50 mL) wasadded n-BuLi (2.4 M, 12.5 mL, 30.11 mmol) under nitrogen at −78° C. Themixture was stirred at −78° C. for 15 minutes. To the resulting mixturewas quickly added diethyl oxalate (16.0 g, 109.5 mmol). The reactionmixture was stirred at −78° C. for 1 h., quenched with saturatedammonium chloride solution (30 mL), and extracted with ethyl acetate(100 mL×3). The combined organic phases were washed with water (50 mL)and brine (50 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated to furnish a crude product, which was further purified withflash column chromatography on silica gel (petroleum ether, 100% v/v) tofurnish Compound 12B. LC-MS (ESI) m/z: 283 [M+H]⁺, 305 [M+Na]⁺; ¹H-NMR(CDCl₃, 400 MHz): δ (ppm) 1.44 (t, J=7.2 Hz, 3H), 2.75 (s, 3H), 4.45 (q,J=7.1 Hz, 2H), 7.39 (d, J=9.0 Hz, 1H), 7.80-7.83 (m, 2H).

Compounds 12C, 12D, 12E, and 12F were synthesized by employing theprocedure described for Compounds 1D, 1E, 1F, and 1G using Compounds12B, 12C, 12D, and 12E in lieu of Compounds 1C, 0.1D, 1E, and 1F.

Compound 12C. LC-MS (ESI) m/z: 361 [M+H]⁺, 383 [M+Na]⁺; ¹H-NMR (CDCl₃,400 MHz): δ (ppm) 1.46 (t, J=7.2 Hz, 3H), 4.47 (q, J=7.2 Hz, 2H), 5.14(s, 2H), 7.49 (dd, J=8.8, 2.0 Hz, 1H), 7.88 (d, J=2.0 Hz, 1H), 7.95 (d,J=8.8 Hz, 1H).

Compound 12D. LC-MS (ESI) m/z: 466 [M+Na]⁺.

Compound 12E. LC-MS (ESI) m/z: 296 [M+H]⁺.

Compound 12F. LC-MS (ESI) m/z: 268 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ(ppm) 5.55 (s, 2H), 7.55 (d, J=8.6 Hz, 1H), 7.97 (d, J=8.6 Hz, 1H), 8.30(s, 1H).

Compound 12 was synthesized by employing the procedure described forCompound 8 using Compound 12F in lieu of Compound 8F. LC-MS (ESI) m/z:544 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ (ppm) 0.57-0.81 (m, 4H),1.96-2.07 (m, 2H), 2.15-2.22 (m, 2H), 3.18-3.32 (m, 2H), 3.36-3.49 (m,1H), 3.63-3.84 (m, 4H), 4.61 (dt, J=11.2, 3.2 Hz, 1H), 4.92-4.96 (m,1H), 5.45-5.57 (m, 2H), 7.16-7.19 (m, 2H), 7.31 (t, J=8.4 Hz, 1H),7.45-7.48 (m, 1H), 7.83 (d, J=8.8 Hz, 1H), 8.03 (s, 1H).

Example 13

Compound 13 was synthesized by employing the procedure described forCompound 8 using Compound 12F and Intermediate A in lieu of Compound 8Fand Intermediate D. LC-MS (ESI) m/z: 560 [M+H]; ¹H-NMR (CD₃OD, 400 MHz):δ (ppm) 0.61-0.75 (m, 4H), 2.00-2.03 (m, 2H), 2.16-2.20 (m, 2H),3.19-3.31 (m, 2H), 3.48-3.51 (m, 1H), 3.65-3.80 (m, 4H), 4.57-5.59 (m,1H), 4.92-4.96 (m, 1H), 5.46-5.56 (m, 2H), 7.28-7.32 (m, 2H), 7.43-7.47(m, 2H), 7.80-7.83 (m, 1H), 8.00-8.02 (m, 1H).

Example 14

Compound 14 was synthesized by employing the procedure described forCompound 8 using Intermediate F in lieu of Intermediate D. LC-MS (ESI)m/z: 552 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ (ppm) 0.62-0.79 (m, 4H),1.99-2.25 (m, 4H), 3.18-3.31 (m, 2H), 3.48-3.55 (m, 1H), 3.66-3.85 (m,4H), 4.64-4.71 (m, 1H), 4.93 (d, J=3.2 Hz, 1H), 5.02-5.12 (m, 2H),7.00-7.04 (m, 3H), 7.34-7.41 (m, 4H), 7.51-7.54 (m, 2H).

Example 15

Compound 15 was synthesized by employing the procedure described forCompound 8 using Compound 12F and Intermediate E in lieu of Compound 8Fand Intermediate D. LC-MS (ESI) m/z: 530 [M+H]⁺; ¹H-NMR (CD₃OD, 400MHz): δ (ppm) 0.59-0.73 (m, 4H), 2.42-2.44 (m, 1H), 2.54-2.59 (m, 1H),3.54-3.57 (m, 2H), 3.76-3.79 (m, 1H), 4.18-4.31 (m, 4H), 4.40-4.45 (m,1H), 4.96-4.98 (m, 1H), 5.44-5.55 (m, 2H), 7.15-7.18 (m, 2H), 7.30 (t,J=8.4 Hz, 1H), 7.44-7.46 (m, 1H), 7.79-7.82 (m, 1H), 7.79-8.01 (m, 1H).

Example 16

Compound 16 was synthesized by employing the procedure described forCompound 8 using Compound 12F and Intermediate B in lieu of Compound 8Fand Intermediate D. LC-MS (ESI) m/z: 546 [M+H]⁺; ¹H-NMR (CD₃OD, 400MHz): δ (ppm) 0.59-0.77 (m, 4H), 2.42-2.44 (m, 1H), 2.56-2.59 (m, 1H),3.56-3.59 (m, 2H), 3.77-3.79 (m, 1H), 4.24-4.27 (m, 4H), 4.40-4.44 (m,1H), 4.96-4.98 (m, ¹H), 5.46-5.55 (m, 2H), 7.32 (s, 2H), 7.43-7.47 (m,2H), 7.80-7.82 (m, 1H), 8.00 (d, J=1.7 Hz, 1H).

Example 17

Compound 17 was synthesized by employing the procedure described forCompound 8 using Compound 1G and Intermediate I in lieu of Compound 8Fand Intermediate D. LC-MS (ESI) m/z: 562 [M+H]⁺; ¹H-NMR ((CD₃)₂CO, 400MHz): δ (ppm) 0.56-0.87 (m, 4H), 2.10-2.34 (m, 4H), 3.19-3.28 (m, 3H),3.36-3.58 (m, 2H), 3.68-4.56 (m, 5H), 4.96-5.70 (m, 4H), 6.44-7.00 (m,1H), 7.06-7.62 (m, 7H), 7.73-7.81 (m, 2H), 8.64-9.31 (m, 1H).

Example 18

Compound 18 was synthesized by employing the procedure described forCompound 8 using Intermediate I in lieu of Intermediate D. LC-MS (ESI)m/z: 585 [M+H]⁺; ¹H-NMR ((CD₃)₂CO, 400 MHz): δ (ppm) 0.62-0.86 (m, 4H),2.06-2.15 (m, 4H), 3.09-3.19 (m, 5H), 3.64-4.14 (m, 5H), 5.00-5.39 (m,3H), 5.58-6.30 (m, 1H), 6.95-7.85 (m, 8H), 11.14-11.60 (m, 1H).

Example 19

Compound 19 was synthesized by employing the procedure described forCompound 8 using Compound 1G and Intermediate H in lieu of Compound 8Fand Intermediate D. LC-MS (ESI) m/z: 578 [M+H]⁺. ¹H-NMR (CD₃OD, 400MHz): δ (ppm) 0.56-0.84 (m, 4H), 2.07-2.21 (m, 4H), 3.16-3.34 (m, 3H),3.44 (s, 1H), 3.53-4.18 (m, 5H), 4.84-5.18 (m, 4H), 5.51-6.11 (m, 1H),6.99-7.08 (m, 1H), 7.15-7.17 (m, 1H), 7.22-7.28 (m, 2H), 7.41-7.57 (m,4H), 7.69-7.77 (m, 2H).

Example 20

To a suspension of LiAlH₄ (2.54 g, 66.8 mmol) in anhydrous THF (100 mL)at 0° C. was added dropwise a solution of Compound 20A (5.0 g, 26.7mmol) in THF (100 mL) over 30 min. The mixture was stirred at roomtemperature overnight. The reaction mixture was quenched with water(2.54 mL), aq. NaOH (15%, 2.54 mL), and water (7.62 mL). After stirringfor 30 min, the mixture was filtered and the filtrate was extracted withethyl acetate (100 mL×3). The combined organic layers were washed withwater (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate,filtered, and concentrated to afford Compound 20B. LC-MS (ESI) nm/z: 174[M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 1.59 (s, 2H), 4.36 (s, 1H),4.85 (s, 2H), 7.04 (s, 1H), 7.24 (t, J=7.2 Hz, 1H), 7.38 (t, J=8.0 Hz,1H), 7.59-7.61 (m, 2H), 7.69 (d, J=8.0 Hz, 1H).

To a solution of Compound 20B (1.0 g, 10 mmol) in water (6 mL), acetone(6 mL), and concentrated HCl (3.2 mL) at 0° C. was added a solution ofNaNO₂ (439 mg, 6.36 mmol) in water (1.4 mL). After the mixture wasstirred at 0° C. for 2 h, to it was added a solution of KI (1.44 g, 8.67mmol) and concentrated H₂SO₄ (0.32 mL) in water (2.4 mL). The mixturewas stirred at 60° C. for 3 h. The reaction mixture was cooled down toroom temperature and a saturated solution of Na₂S₂O₃ (10 mL) was added.The mixture was extracted with ethyl acetate (100 mL×3). The organiclayer was washed with water (10 mL) and brine (10 mL), dried overanhydrous sodium sulfate, filtered, and concentrated to yield a crudeproduct. The crude product was purified with flash column chromatographyon silica gel (ethyl acetate in petroleum ether, 20% v/v) to furnishCompound 20C. LC-MS (ESI) m/z: 285 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ(ppm) 2.17 (t, J=6.0 Hz, 1H), 4.83 (d, J=6.4 Hz, 2H), 7.48-7.53 (m, 2H),7.72-7.74 (m, 1H), 7.81-7.84 (m, 1H), 7.90 (s, 1H), 8.38 (s, 1H).

To a solution of Compound 20C (568 g, 2.0 mmol) in dichloromethane (20mL) was added triphenylphosphine (786 mg, 3.0 mmol), iodine (762 mg, 3.0mmol), and imidazole (204 mg, 3.0 mmol). The mixture was stirred at roomtemperature overnight. The resulting solution was quenched withsaturated Na₂S₂O₃ solution (10 mL) and extracted with dichloromethane(50 mL×3). The organic layer was washed with water (10 mL) and brine (10mL), dried over anhydrous sodium sulfate, filtered, and concentrated toyield a crude product. The crude was purified with flash columnchromatography on silica gel (ethyl acetate in petroleum ether, 3% v/v)to give Compound 20D. ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 4.74 (s, 2H),7.49-7.51 (m, 2H), 7.69-7.72 (m, 1H), 7.76-7.78 (m, 1H), 7.98 (s, 1H),8.38 (s, 1H).

To a suspension of Compound 20D (3.8 g, 9.64 mmol) in AcOH (60 mL) wasadded zinc powder (6.27 g, 96.4 mmol). The mixture was stirred at 80° C.for 2 h. The resulting solution was cooled down to room temperature andfiltered with Celite. After removal of the solvent, the residue wasextracted with ethyl acetate (100 mL×3). The organic layer was washedwith water (10 mL) and brine (10 mL), dried over anhydrous sodiumsulfate, filtered, and concentrated to yield a crude product. The crudewas purified with flash column chromatography on silica gel (petroleumether, 100%) to furnish Compound 20E. ¹H-NMR (CDCl₃, 400 MHz): δ (ppm)2.59 (s, 3H), 7.41-7.49 (m, 2H), 7.69-7.74 (m, 3H), 8.38 (s, 1H).

Compound 20F was synthesized by employing the procedure described forCompound 12B using Compound 20E in lieu of Compound 12A. LC-MS (ESI)m/z: 243 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 1.46 (t, J=7.2 Hz,3H), 2.75 (s, 3H), 4.50 (q, J=7.2 Hz, 2H), 7.51 (t, J=8.4 Hz, 1H), 7.62(t, J=8.4 Hz, 1H), 7.71 (s, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.90 (d, J=8.0Hz, 1H), 8.28 (s, 1H).

Compounds 20G, 20H, 20I, 20J, and 20 were synthesized by employing theprocedure described for Compounds 1D, 1E, 1F, 1G, and 1 using Compounds20F, 20G, 20H, 20I, and 20J in lieu of Compounds 1C, 1D, 1E, 1F, and 1G.

Compound 20G. LC-MS (ESI) m/z: 321 [M+H]⁺; 1.47 (t, J=7.2 Hz, 3H), 4.52(q, J=7.2 Hz, 2H), 5.11 (s, 2H), 7.59-7.73 (m, 2H), 7.88 (d, J=8.0 Hz,1H), 7.94 (s, 1H), 7.98 (d, J=8.0 Hz, 1H), 8.36 (s, 1H).

Compound 20H. LC-MS (ESI) m/z: 404 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ(ppm) 1.47 (t, J=7.2 Hz, 3H), 4.52 (q, J=7.2 Hz, 2H), 5.79 (s, 2H), 7.61(t, J=8.0 Hz, 1H), 7.68 (t, J=8.4 Hz, 1H), 7.73-7.75 (m, 2H), 7.82-7.84(m, 2H), 7.92 (d, J=8.0 Hz, 1H), 7.96 (d, J=8.0 Hz, 1H), 8.28 (s, 1H),8.44 (s, 1H).

Compound 20I. LC-MS (ESI) m/z: 256 [M+H]⁺.

Compound 20J. LC-MS (ESI) m/z: 228 [M+H.

Compound 20. LC-MS (ESI) m/z: 520 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ(ppm) 0.39-0.64 (m, 4H), 1.96-2.11 (m, 4H), 3.13-3.17 (m, 2H), 3.45-3.71(m, 5H), 4.66-4.69 (m, 1H), 4.87 (d, J=2.4 Hz, 1H), 5.02-5.14 (m, 2H),7.17 (d, J=8.4 Hz, 1H), 7.27 (dd, J=8.4, 2.0 Hz, 1H), 7.41-7.51 (m, 3H),7.60 (s, 1H), 7.69 (s, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.79 (d, J=8.0 Hz,1H).

Example 21

Compound 21 was synthesized by employing the procedure described forCompound 8 using Compound 1G and Intermediate J in lieu of Compound 8Fand Intermediate D. LC-MS (ESI) m/z: 564 [M+H]⁺; ¹H-NMR ((CD₃)₂CO, 400MHz): δ (ppm) 0.54-0.87 (m, 4H), 2.55-2.72 (m, 2H), 3.12-3.25 (m, 3H),3.67-4.12 (m, 3H), 4.41-4.64 (m, 4H), 4.83-5.16 (m, 3H), 5.28-5.49 (m,1H), 6.36-7.60 (m, 8H), 7.73-7.80 (m, 2H).

Example 22

Dimethylformamide (8.0 mL, 100 mmol) was added dropwise to a solution ofphosphorus tribromide (8.0 mL, 84 mmol) in dry chloroform (200 mL) at 0°C. The mixture was stirred at 0° C. for 1 h to give a suspension. Asolution of β-tetralone (22A, 5.0 g, 34 mmol) in dry chloroform (200 mL)was added to the suspension and the reaction mixture was heated atreflux for 1 h. The reaction mixture was cooled to 0° C. and basifiedwith saturated aqueous sodium bicarbonate solution. The resultingmixture was extracted with dichloromethane, dried over anhydrous sodiumsulfate, filtered, and evaporated under vacuum. The residue was purifiedwith flash column chromatography on silica gel (ethyl acetate inpetroleum ether, 25% v/v) to give Compound 22B. ¹H-NMR (DMSO-d₆, 400MHz): δ (ppm) 2.85-2.89 (m, 2H), 3.00-3.04 (m, 2H), 7.21-7.27 (m, 3H),7.79-7.81 (m, 1H), 10.18 (s, 1H).

A mixture of Compound 22B (3.1 g, 13 mmol) and DDQ (2.9 g, 13 mmol) intoluene (100 mL) was refluxed for 72 h. After the reaction mixture wascooled to room temperature, the mixture was filtered through Celite andthe filtrate was evaporated to dryness. The residue was purified withflash column chromatography on silica gel (ethyl acetate in petroleumether, 25% v/v) to give Compound 22C. LC-MS (ESI) m/z: No; ¹H-NMR(DMSO-d₆, 400 MHz): δ (ppm) 7.65-7.80 (m, 3H), 8.06-8.08 (m, 1H),8.15-8.17 (m, 1H), 8.85-8.87 (m, 1H), 10.62 (s, 1H).

To a solution of Compound 22C (2.44 g, 10.4 mmol) in EtOH (50 mL) atroom temperature was added NaBH₄ (395 mg, 10.4 mmol) in severalportions. The mixture was stirred at room temperature for 2 h. Thereaction mixture was quenched with 1 N HCl, evaporated, and purifiedwith flash column chromatography on silica gel (ethyl acetate inpetroleum ether, 50% v/v) to give Compound 22D. LC-MS (ESI) m/z: 219[M-OH]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 5.30 (d, J=6.0 Hz, 2H),7.50-7.68 (m, 4H), 7.83 (d, J=7.6 Hz, 1H), 8.24 (d, J=8.4 Hz, 1H).

Compounds 22E and 22F were synthesized by employing the proceduredescribed for Compounds 20D and 20E using Compounds 22D and 22E in lieuof Compounds 20C and 20D.

Compound 22E. ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 5.04 (s, 2H), 7.53-7.58(m, 2H), 7.66-7.69 (m, 2H), 7.85-7.87 (m, 1H), 8.05-8.07 (m, 1H).

Compound 22F. ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 2.80 (s, 3H), 7.49-7.62(m, 4H), 7.81 (d, J=8.0 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H).

Compound 22G was synthesized by employing the procedure described forCompound 12B using Compound 22F in lieu of Compound 12A. LC-MS (ESI)m/z: 243 [M+H]⁺.

Compounds 22H, 22I, 22J, 22K, and 22 were synthesized by employing theprocedures described for Compounds 1D, 1E, 1F, 1G, and 1 using Compounds22G, 22H, 22I, 22J, and 22K in lieu of Compounds 1C, 1D, 1E, 1F, and 1G.

Compound 22H. LC-MS (ESI) m/z: 321 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ(ppm) 1.43 (t, J=7.2 Hz, 3H), 4.48 (q, J=7.2 Hz, 2H), 5.32 (s, 2H),7.65-7.73 (m, 3H), 7.91-7.94 (m, 2H), 8.33-8.35 (m, 1H).

Compound 22I. LC-MS (ESI) m/z: 404 [M+H]⁺.

Compound 22J. LC-MS (ESI) m/z: 256 [M+H]⁺.

Compound 22K. LC-MS (ESI) m/z: 228 [M+H]⁺.

Compound 22. LC-MS (ESI) m/z: 520 [M+H]⁺; ¹H-NMR (acetone-d₆, 400 MHz):δ (ppm) 0.68-0.69 (m, 2H), 0.79-0.80 (m, 2H), 2.07-2.09 (m, 4H), 3.08(brs, 2H), 3.75-3.79 (m, 2H), 3.93-3.97 (m, 3H), 4.81-4.82 (m, 1H), 5.20(d, J=1.6 Hz, 1H), 5.53 (q, J=15.2 Hz, 2H), 7.33-7.35 (m, 1H), 7.43-7.45(m, 1H), 7.54-7.55 (m, 1H), 7.64-7.66 (m, 2H), 7.77-7.78 (m, 1H),7.87-7.97 (m, 1H), 7.96-8.03 (m, 2H), 8.11-8.14 (m, 1H).

Example 23

To a solution of Compound 23A (1.35 g, 10 mmol) in MeCN (10 mL) at 0° C.was added dropwise a solution of NBS (1.78 g, 10 mmol) in MeCN (10 mL)over 3 min. and the reaction mixture was stirred at room temperature for3 h. After removal of solvent, the residue was filtered through a shortplug of silica (eluting with ethyl acetate in petroleum ether, 20% v/v).The filtrate was concentrated to yield Compound 23B. LC-MS (ESI) m/z:214 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 2.57 (s, 3H), 6.30 (s, 2H),6.57 (d, J=8.8 Hz, 1H), 7.33 (dd, J=8.8, 2.4 Hz, 1H), 7.81 (d, J=2.0 Hz,1H).

Compound 23C was synthesized by employing the procedure described forCompound 1B using Intermediate 23B in lieu of Intermediate 1A. LC-MS(ESI) m/z: 230 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 2.65 (s, 3H),6.35 (s, 2H), 6.74 (d, J=8.8 Hz, 1H), 7.12 (t, J=8.4 Hz, 2H), 7.46-7.50(m, 3H), 7.86 (d, J=2.4 Hz, 1H).

To a stirred solution of p-TsOH (1.03 g, 6.0 mmol) in MeCN (7.2 mL) wasadded Compound 23C (458 mg, 2.0 mmol). To the resulting suspension at 0°C. was slowly added dropwise an aqueous solution of KI (830 mg, 5.0mmol) and NaNO₂ (276 mg, 4.0 mmol) in water (2 mL). The mixture wasstirred at room temperature for 4.5 h. and water (15 mL) and saturatedNa₂S₂O₃ solution (10 mL) were added. The mixture was extracted withethyl acetate (100 mL×3). The organic layer was washed with water (10mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered,and concentrated to yield a crude product. The crude product waspurified with flash column chromatography on silica gel (ethyl acetatein petroleum ether, 10% v/v) to furnish Compound 23D. LC-MS (ESI) m/z:341 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 2.68 (s, 3H), 7.16 (t,J=8.4 Hz, 2H), 7.30 (dd, J=8.0, 2.4 Hz, 1H), 7.51-7.55 (m, 2H), 7.58 (d,J=2.4 Hz, 1H), 7.98 (d, J=8.8 Hz, 1H).

To a solution of methyltriphenylphosphonium bromide (1.76 g, 4.94 mmol)in THF (40 mL) at 0° C. was added n-BuLi (2.5 M in hexane, 1.98 mL, 4.94mmol). After stirring at 0° C. for 1 h, to the mixture was added asolution of Compound 23D (1.12 g, 3.31 mmol) in THF (5 mL). The mixturewas stirred at room temperature for 2 h. The reaction mixture wasquenched with saturated ammonium chloride solution (10 mL) and extractedwith ethyl acetate (100 mL×3). The organic layer was washed with water(10 mL) and brine (10 mL), dried over anhydrous sodium sulfate,filtered, and concentrated to yield a crude product. The crude waspurified with flash column chromatography on silica gel (petroleumether, 100%) to give Compound 23E. ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 2.11(s, 3H), 4.95 (s, 1H), 5.27 (t, J=1.6 Hz, 1H), 7.11-7.15 (m, 3H), 7.35(d, J=2.0 Hz, 1H), 7.51-7.55 (m, 2H), 7.88 (d, J=8.0 Hz, 1H).

Compound 23F was' synthesized by employing the procedure described forCompound 12B using Compound 23E in lieu of Compound 12A. LC-MS (ESI)m/z: 313 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 1.38 (t, J=7.2 Hz,3H), 2.21 (s, 3H), 4.33 (q, J=7.2 Hz, 2H), 4.86 (s, 1H), 5.27 (s, 1H),7.18 (t, J=8.4 Hz, 2H), 7.52 (t, J=1.6 Hz, 1H), 7.59-7.62 (m, 3H), 7.83(d, J=8.4 Hz, 1H).

To a solution of Compound 23F (550 mg, 1.76 mmol) in ethanol (20 mL) wasadded sodium acetate (444 mg, 5.28 mmol) and hydroxylamine hydrochloride(364 mg, 5.28 mmol). The mixture was heated at 50° C. for 3 h. Afterremoval of the solvent, it was extracted with ethyl acetate (50 mL×3).The organic layer was washed with water (10 mL) and brine (10 mL), driedover anhydrous sodium sulfate, filtered, and concentrated to yield acrude product. The crude was purified with flash column chromatographyon silica gel (ethyl acetate in petroleum ether, 10% v/v) to furnishCompound 23G. LC-MS (ESI) m/z: 328 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ(ppm) 1.37 (t, J=7.2 Hz, 3H), 1.54 (s, 6H), 4.38 (q, J=7.2 Hz, 2H), 7.34(t, J=8.8 Hz, 2H), 7.75 (dd, J=8.4, 1.6 Hz, 1H), 7.78-7.82 (m, 2H), 7.90(d, J=8.4 Hz, 1H), 7.92 (d, J=1.2 Hz, 1H).

Compounds 23H and 23 were synthesized by employing the proceduresdescribed for Compounds 1G and 1 using Compounds 23G and 22K in lieu ofCompounds 1F and 1G.

Compound 23H. LC-MS (ESI) m/z: 300 [M+H]⁺.

Compound 23. LC-MS (ESI) m/z: 592 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ(ppm) 0.54-0.76 (m, 4H), 1.66 (s, 3H), 1.72 (s, 3H), 2.02-2.19 (m, 4H),3.21-3.28 (m, 2H), 3.55-3.84 (m, 4H), 3.96-3.99 (m, 1H), 4.62-4.65 (m,1H), 4.97 (d, J=1.6 Hz, 1H), 7.21 (t, J=8.8 Hz, 2H), 7.32-7.35 (m, 1H),7.49 (d, J=1.6 Hz, 1H), 7.64-7.74 (m, 5H), 8.16 (d, J=8.0 Hz, 1H).

Example 24

Compounds 24B, 24C, 24D, 24E, 24F, 24G, and 24 were synthesized byemploying the procedure described for Compounds 1B, 1C, 1D, 1E, 1F, 1G,and 1 using Compounds 24A, 24B, 24C, 24D, 24E, 24F, and 24G in lieu ofCompounds 1A, LB, 1C, 1D, 1E, 1F, and 1G.

Compound 24B. ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 1.28 (t, J=7.6 Hz, 3H),2.68-2.74 (m, 2H), 7.11 (t, J=8.8 Hz, 2H), 7.18-7.20 (m, 1H), 7.34-7.37(m, 3H), 7.53-7.54 (m, 2H).

Compound 24C. LC-MS: (ESI) m/z: 301 [M+H]⁺.

Compound 24D. ¹H-NMR (CDCl₃, 400 MHz): & (ppm) 1.42-1.46 (m, 3H), 2.07(d, J=6.8 Hz, 3H), 4.44-4.49 (m, 2H), 6.19-6.25 (m, 1H), 7.17-7.21 (m,2H), 7.55-7.64 (m, 3H), 7.71-7.73 (d, J=8.4 Hz, 1H), 8.08-8.09 (d, J=2.0Hz, 1H).

Compound 24E. LC-MS: (ESI) m/z: 484 [M+Na]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ(ppm) 1.39 (t, J=7.2 Hz, 3H), 1.74 (d, J=6.4 Hz, 3H), 4.39-4.44 (m, 2H),6.26-6.31 (m, 2H), 7.20-7.25 (m, 1H), 7.59-7.62 (m, 1H), 7.70-7.86 (m,7H), 8.49 (d, J=1.6 Hz, 1H).

Compound 24F. LC-MS: (ESI) m/z: 314 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ(ppm) 1.45 (t, J=7.6 Hz, 3H), 1.72 (d, J=6.4 Hz, 3H), 4.50 (m, 2H),5.15-5.19 (m, 1H), 7.16 (t, J=8.8 Hz, 2H), 7.33 (s, 1H), 7.55-7.61 (m,3H), 7.99 (d, J=8.0 Hz, 1H).

Compound 24G. LC-MS: (ESI) m/z: 286 [M+H]⁺.

Compound 24. LC-MS (ESI) m/z: 578 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ(ppm) 0.54-0.69 (m, 4H), 1.56-1.58 (m, 3H), 1.95-2.10 (m, 4H), 3.10-3.15(m, 2H), 3.43-3.47 (m, 1H), 3.60-3.71 (m, 4H), 4.59-4.62 (m, 1H), 4.84(t, J=2.8 Hz, 1H), 5.08-5.15 (m, 1H), 7.10 (t, J=8.4 Hz, 2H), 7.21-7.27(m, 3H), 7.37-7.45 (m, 3H), 7.58-7.62 (m, 2H).

Example 25

Compound 25 was synthesized by employing the procedure described forCompound 1 using Compound 22K and Intermediate F in lieu of Compound 1Gand Intermediate A. LC-MS (ESI) m/z: 486 [M+H]⁺; ¹H-NMR (acetone-d₆, 400MHz): δ (ppm) 0.73-0.75 (m, 4H), 2.13 (s, 4H), 3.01-3.10 (m, 2H),3.38-3.40 (m, 2H), 3.68-3.93 (m, 3H), 4.65 (s, 1H), 5.08 (s, 1H),5.38-5.56 (m, 2H), 7.01-7.03 (m, 2H), 7.31-7.35 (m, 2H), 7.58-7.63 (m,3H), 7.77-7.80 (m, 1H), 7.87-7.88 (m, 2H).

Example 26

Compound 26 was synthesized by employing the procedure described forCompound 1 using Compound 22K and Intermediate B in lieu of Compound 1Gand Intermediate A. LC-MS (ESI) m/z: 506 [M+H]⁺; ¹H-NMR (acetone-d₆, 400MHz): δ (ppm) 0.67-0.82 (m, 4H), 2.48-2.66 (m, 2H), 3.70-3.77 (m, 2H),3.85-3.88 (m, 1H), 4.36-4.42 (m, 4H), 4.66-4.67 (m, 1H), 5.15 (s, 1H),5.49-5.55 (m, 2H), 7.33-7.35 (m, 1H), 7.41-7.44 (m, 1H), 7.52-7.53 (m,1H), 7.64-7.67 (m, 2H), 7.80-7.82 (m, 1H), 7.87-7.93 (m, 2H), 7.98-8.01(m, 1H), 8.11-8.14 (m, 1H).

Example 27

A mixture of Compound 27A (13.50 g, 70.58 mmol), propane-1,2,3-triol(7.98 g, 86.74 mmol), and NaI (1.06 g, 7.06 mmol) in H₂SO₄ (80%, 39.90g) was stirred at 140° C. for 4 hours. The reaction mixture was cooleddown to room temperature, adjusted pH to 11 with aqueous NaOH solution(40%, 60 mL), and extracted with dichloromethane (200 mL×3). Thecombined organic phases were washed with water (200 mL) and brine (200mL), dried over anhydrous sodium sulfate, concentrated, and purifiedwith flash column chromatography on silica gel (ethyl acetate inpetroleum ether, from 0% to 10%) to furnish Compound 27B. LC-MS (ESI)m/z: 222 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 2.94 (s, 3H), 7.42(dd, J=8.0, 4.0 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H),8.11 (dd, J=8.4, 2.0 Hz, 1H), 8.94 (dd, J=4.0, 1.6 Hz, 1H).

Compound 27C was synthesized by employing the procedure described forCompound 12B using Compound 27B in lieu of Compound 12A. LC-MS (ESI)m/z: 244 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 1.44 (t, J=7.2 Hz,3H), 3.04 (s, 3H), 4.47 (q, J=6.8 Hz, 2H), 7.52 (dd, J=8.0, 2.0 Hz, 1H),7.72-7.75 (m, 2H), 8.17 (dd, J=8.4, 2.0 Hz, 1H), 9.03 (dd, J=4.0, 1.6Hz, 1H).

Compounds 27D, 27E, 27F, and 27G were synthesized by employing theprocedure described for Compounds 1D, 1E, 1F, and 1G using Compounds27C, 27D, 27E, and 24F in lieu of Compounds 1C, 1D, 1E, and 1F.

Compound 27D. LC-MS (ESI) m/z: 322 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ(ppm) 1.45 (t, J=7.6 Hz, 3H), 4.49 (q, J=7.6 Hz, 2H), 5.67 (s, 2H), 7.57(dd, J=8.0, 4.0 Hz, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.90 (d, J=8.8 Hz, 1H),8.21 (dd, J=8.4, 1.6 Hz, 1H), 9.12 (dd, J=4.0, 1.6 Hz, 1H).

Compound 27E. LC-MS (ESI) m/z: 405 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ(ppm) 1.39 (t, J=7.6 Hz, 3H), 4.46 (q, J=7.2 Hz, 2H), 6.27 (s, 2H), 7.48(dd, J=8.4, 4.4 Hz, 1H), 7.67-7.74 (m, 4H), 7.77 (d, J=8.4 Hz, 1H), 7.94(d, J=8.4 Hz, 1H), 8.19 (dd, J=8.4, 1.6 Hz, 1H), 8.90 (dd, J=4.4, 1.6Hz, 1H).

Compound 27F. LC-MS (ESI) m/z: 257 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ(ppm) 1.47 (t, J=6.8 Hz, 3H), 4.50 (q, J=7.2 Hz, 2H), 5.80 (s, 2H), 7.52(dd, J=8.4, 4.4 Hz, 1H), 7.87 (d, J=8.4 Hz, 1H), 8.09 (d, J=8.4 Hz, 1H),8.20 (dd, J=8.0, 1.6 Hz, 1H), 8.98 (dd, J=4.0, 1.2 Hz, 1H).

Compound 27G. LC-MS (ESI) m/z: 229 [M+H]⁺.

Compound 27 was synthesized by employing the procedure described forCompound 8 using Compound 27G and Intermediate A in lieu of Compound 8Fand Intermediate D. LC-MS (ESI) m/z: 521 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400MHz): δ (ppm) 0.65-0.81 (m, 4H), 1.88-2.05 (m, 4H), 3.12-3.21 (m, 2H),3.44-3.57 (m, 4H), 3.88-3.91 (m, 1H), 4.58-4.61 (m, 1H), 4.83 (d, J=2.8Hz, 1H), 5.52 (d, J=14.0 Hz, 1H), 5.83 (d, J=14.0 Hz, 1H), 7.32-7.38 (m,2H), 7.44 (d, J=2.0 Hz, 1H), 7.69-7.74 (m, 2H), 8.02 (d, J=8.4 Hz, 1H),8.48-8.50 (m, 2H), 9.03 (dd, J=4.0, 1.6 Hz, 1H), 9.25 (brs, 1H).

Example 28

Compounds 28B, 28C, and 28D were synthesized by employing the proceduresdescribed for Compounds 22B, 22C, and 22D using Compounds 28A, 28B, and28C in lieu of Compounds 22A, 22B, and 22C.

Compound 28B. LC-MS (ESI) m/z: No; ¹H-NMR (CDCl₃, 400 MHz): δ (ppm)2.87-2.91 (m, 2H), 3.00-3.04 (m, 2H), 6.85-6.88 (m, 1H), 6.91-6.96 (m,1H), 7.99-8.02 (m, 1H), 10.30 (s, 1H).

Compound 28C. LC-MS (ESI) m/z: No; ¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm)7.44-7.47 (m, 2H), 7.71 (d, J=8.8 Hz, 1H), 7.81 (d, J=8.8 Hz, 1H),9.13-9.17 (m, 1H), 10.74 (s, 1H).

Compound 28D. LC-MS (ESI) m/z: 237 [M-OH]⁺.

Compounds 28E and 28F were synthesized by employing the proceduredescribed for Compounds 20D and 22E using Compounds 28D and 28E in lieuof Compounds 20C and 20D.

Compound 28E. ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 4.99 (s, 2H), 7.41-7.46(m, 2H), 7.56-7.62 (m, 2H), 8.04-8.07 (m, 1H).

Compound 28F. ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 2.78 (s, 3H), 7.27-7.32(m, 1H), 7.39-7.42 (m, 1H), 7.48 (d, J=8.8 Hz, 1H), 7.61 (d, J=8.8 Hz,1H), 8.00-8.04 (m, 1H).

Compound 28G was synthesized by employing the procedure described forCompound 12B using Compound 28F in lieu of Compound 12A. LC-MS (ESI)m/z: 261 [M+H]⁺; ¹H-NMR: (CDCl₃, 400 MHz): δ (ppm) 1.43 (t, J=8.4 Hz,3H), 2.90 (s, 3H), 4.46 (q, J=6.8 Hz, 2H), 7.35-7.40 (m, 1H), 7.46-7.49(m, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 8.22-8.26 (m,1H).

Compounds 28H, 28I, 28J, and 28K were synthesized by employing theprocedures described for Compounds 1D, 1E, 1F, and 1G using Compounds28G, 28H, 28I, and 28J in lieu of Compounds 1C, 1D, 1E, and 1F.

Compound 28H. ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 1.37 (t, J=6.8 Hz, 3H),4.41 (q, J=7.2 Hz, 2H), 5.23 (s, 2H), 7.40-7.47 (m, 2H), 7.62 (d, J=8.8Hz, 1H), 7.80 (d, J=8.4 Hz, 1H), 8.28-8.31 (m, 1H).

Compound 28I. LC-MS (ESI) m/z: 422 [M+H]⁺.

Compound 28J. LC-MS (ESI) m/z: 274 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ(ppm) 1.47 (t, J=6.8 Hz, 3H), 4.50 (q, J=6.8 Hz, 2H), 5.51 (s, 2H),7.37-7.42 (m, 1H), 7.52-7.55 (m, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.90-7.93(m, 1H), 7.99 (d, J=8.8 Hz, 1H).

Compound 28K. LC-MS (ESI) nm/z: 246 [M+H]⁺.

Compound 28 was synthesized by employing the procedure described forCompound 8 using Compound 28K and Intermediate A in lieu of Compound 8Fand Intermediate D. LC-MS (ESI) m/z: 538 [M+H]⁺: ¹H-NMR (MeOD, 400 MHz):δ (ppm) 0.74-0.82 (m, 4H), 1.85-1.86 (m, 4H), 2.68-3.09 (m, 6H),3.81-3.87 (m, 1H), 4.43-4.49 (m, 1H), 4.94-4.95 (m, 1H), 5.51 (s, 2H),7.27-7.34 (m, 2H), 7.44-7.53 (m, 2H), 7.52 (d, J=8.8 Hz, 1H), 7.63-7.66(m, 1H), 7.77-7.83 (m, 1H), 8.11-8.16 (m, 1H).

Example 29

Compound 29 was synthesized by employing the procedure described forCompound 8 using Compound 28K and Intermediate F in lieu of Compound 8Fand Intermediate D. LC-MS (ESI) m/z: 504 [M+H]⁺: ¹H-NMR (MeOD, 400 MHz):δ (ppm) 0.67-0.77 (m, 4H), 1.86 (br, 4H), 2.72-2.90 (m, 6H), 3.73-3.78(m, 1H), 4.43-4.53 (m, 1H), 4.93-4.94 (m, 1H), 5.45-5.57 (m, 2H), 7.02(d, J=8.8 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 7.44-7.49 (m, 1H), 7.57 (d,J=8.4 Hz, 1H), 7.63-7.66 (m, 1H), 7.82 (d, J=8.8 Hz, 1H), 8.13-8.16 (m,1H).

Example 30

Compound 30 was synthesized by employing the procedure described forCompound 8 using Compound 28K and Intermediate B in lieu of Compound 8Fand Intermediate D. LC-MS (ESI) m/z: 524 [M+H]. ¹H-NMR (MeOD, 400 MHz):δ (ppm) 0.73-0.82 (m, 4H), 2.14-2.17 (m, 2H), 2.80-2.94 (m, 2H),3.45-3.50 (m, 4H), 3.82-3.87 (m, 1H), 4.29-4.33 (m, 1H), 4.87-4.88 (m,1H), 5.46-5.56 (m, 2H), 7.31-7.36 (m, 2H), 7.45-7.51 (m, 3H), 7.63-7.66(m, 1H), 7.80-7.82 (m, 1H), 8.12-8.16 (m, 1H).

Example 31

Compound 31 was synthesized by employing the procedure described forCompound 8 using Compound 28K and Intermediate G in lieu of Compound 8Fand Intermediate D. LC-MS (ESI) m/z: 490 [M+H]⁺; ¹H-NMR (MeOD, 400 MHz):δ (ppm) 0.67-0.78 (m, 4H), 2.10-2.17 (m, 2H), 2.71-2.85 (m, 2H),3.36-3.42 (m, 4H), 3.73-3.77 (m, 1H), 4.28-4.33 (m, 1H), 4.85-4.86 (m,1H), 5.41-5.57 (m, 2H), 7.02 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.8 Hz, 2H),7.46-7.56 (m, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.62-7.65 (m, 1H), 7.81 (d,J=8.8 Hz, 1H), 8.12-8.15 (m, 1H).

Example 32

To a mixture of 2-fluoro-6-methylbenzoic acid (32A, 8.5 g, 55 mmol) inconcentrated H₂SO₄ (300 mL) at 0° C. was added NBS (10.2 g, 57 mmol).The mixture was stirred at 0° C. for 3 hours. The reaction mixture waspoured into ice water (800 mL) and extracted with ether (500 mL×2). Thecombined organic layers were washed with brine (500 mL), dried overanhydrous sodium sulfate, and concentrated to afford Compound 32B. LC-MS(ESI) m/z: 232.9 [M+H]⁺.

To a solution of Compound 32B (5.0 g, 21.5 mmol) in THF (50 mL) undernitrogen was added trimethyl borate (2.2 g, 21.5 mmol). After it wasstirred for 15 minutes, borane-dimethyl sulfide solution (1 M, 43 mL, 43mmol) was added at 0° C. The mixture was stirred at 80° C. overnight.The reaction mixture was cooled down to room temperature and quenchedwith methanol (5 mL). After removal of solvent, the residue was dilutedwith ethyl acetate (200 mL), washed with saturated aqueous sodiumhydrogen carbonate solution (50 mL) and brine (50 mL), dried overanhydrous sodium sulfate, and concentrated to afford Compound 32C. LC-MS(ESI) m/z: 219 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 2.52 (s, 3H),4.79 (s, 2H), 6.80-6.85 (m, 1H), 7.46-7.50 (m, 1H).

To a solution of Compound 32C (4.0 g, 18.3 mmol) in dichloromethane (100mL) at 0° C. was added Dess-Martin periodinane (11.7 g, 27.5 mmol) inseveral small portions. The mixture was stirred at 10° C. for 16 hours.The reaction mixture was diluted with diethyl ether (300 mL) and pouredinto a saturated aqueous sodium hydrogen carbonate solution (200 mL) at0° C. To the mixture was added saturated aqueous Na₂S₂O₃ solution (300mL) and the reaction mixture was stirred vigorously for 0.5 h. Theorganic phase was separated and the aqueous layer was extracted withdiethyl ether (200 mL×2). The combined organic layers were dried overanhydrous sodium sulfate and evaporated to give Compound 32D. ¹H-NMR(CDCl₃, 400 MHz): δ (ppm) 2.63 (s, 3H), 6.86-6.88 (m, 1H), 7.66-7.69 (m,1H), 10.39 (s, 1H).

To a mixture of Compound 32D (6.05 g, 28 mmol) and potassium carbonate(5.02 g, 36.4 mmol) in DMF (30 mL) with ice cooling was added dropwiseethyl thioglycolate (3.36 g, 28 mmol). The mixture was stirred atambient temperature for 30 minutes and at 60° C. for 12 hours, untilLCMS showed full conversion of starting material. The reaction mixturewas poured into water (500 mL) and extracted with ethyl acetate (500mL×2). The extracts were washed with H₂O (500 mL), dried, andconcentrated under vacuum. The residue was slurried in ethyl alcohol andcollected by filtration to give Compound 32E. ¹H-NMR (CDCl₃, 400 MHz): δ(ppm) 1.42 (t, J=6.8 Hz, 3H), 2.70 (s, 3H), 4.42 (q, J=6.8 Hz, 2H), 7.58(m, 2H), 8.13 (s, 1H).

A mixture of Compound 32E (5.3 g, 18 mmol) and LiOH.H₂O (1.49 g, 36mmol) in THF (40 mL) and H₂O (5 mL) was heated at 40° C. overnight. Thereaction mixture was cooled down to room temperature and concentratedunder vacuum. The residue was dissolved in H₂O (50 mL), adjusted to pH 4with aqueous HCl solution (1 N), and extracted with ethyl acetate (100mL×3). The combined organic layers were dried over anhydrous sodiumsulfate, filtered, and concentrated to afford Compound 32F. LC-MS (ESI)m/z: 270 [M+H]⁺.

To a solution of Compound 32F (810 mg, 2.98 mmol) in quinoline (6 mL)was added Cu powder (95 mg, 1.49 mmol). The mixture was stirred at 200°C. under nitrogen for 4 hours. The reaction mixture was cooled down toroom temperature and filtered to remove the Cu powder. The filtrate wasdiluted with ethyl acetate (100 mL), washed with diluted HCl (50 mL×2)and brine (50 mL), dried over anhydrous sodium sulfate, and concentratedto give a crude product, which was purified with flash columnchromatography on silica gel (petroleum ether, 100% v/v) to affordCompound 32G. ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 2.69 (s, 3H), 7.69 (d,J=8.4 Hz, 1H), 7.45-7.49 (m, 2H), 7.56 (d, J=8.4 Hz, 1H).

To a solution of diisopropylamine (1.71 g, 17 mmol) in THF (30 mL) undernitrogen at −60° C. was added a solution of n-BuLi in hexane (2.5 M,6.76 mL, 17 mmol). After the mixture was stirred at −60° C. for 10minutes, a solution of Compound 32G (3.48 g, 15.3 mmol) in THF (10 mL)was added dropwise. The resulting mixture was stirred for 0.5 hour and asolution of CCl₄ (6 mL) in THF (2 mL) was added in one portion. Afterstirring at −60° C. for 1.5 hour, the reaction mixture was quenched withsaturated ammonium chloride solution (60 mL) and extracted with ethylacetate (100 mL×3). The combined organic layers were washed with brine(100 mL), dried over anhydrous sodium sulfate, and concentrated to givea crude product, which was purified with flash column chromatography onsilica gel (petroleum ether, 100% v/v) to furnish Compound 32H. ¹H-NMR(CDCl₃, 400 MHz): δ (ppm) 2.60 (s, 3H), 7.25 (d, J₁=6.0 Hz, 1H), 7.40(s, 1H), 7.47 (d, J=6.0 Hz, 1H).

Compound 321 was synthesized by employing the procedure described forCompound 12B using Compound 32H in lieu of Compound 12A. LC-MS (ESI)m/z: 305 [M+Na]⁺.

Compounds 32J, 32K, 32L, and 32M were synthesized by employing theprocedures described for Compounds 1D, 1E, 1F, and 1G using Compounds321, 32J, 32K, and 32L in lieu of Compounds 1C, 1D, 1E, and 1F.

Compound 32J. ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 1.45 (t, J=6.4 Hz, 3H),4.46 (q, J=6.4 Hz, 2H), 5.13 (s, 2H), 7.52 (s, 1H), 7.64 (d, J=8.4 Hz,1H), 7.78 (d, J=8.4 Hz, 1H).

Compound 32K. LC-MS (ESI) m/z: 444 [M+H]⁺.

Compound 32L. LC-MS (ESI) m/z: 296 [M+H]⁺.

Compound 32M. LC-MS (ESI) m/z: 268 [M+H]⁺.

Compound 32 was synthesized by employing the procedure described forCompound 8 using Compound 32M and Intermediate A in lieu of Compound 8Fand Intermediate D. LC-MS (ESI) m/z: 560 [M+H]⁺; ¹H-NMR (MeOD, 400 MHz):δ (ppm). 0.67-0.82 (m, 4H), 2.04-2.22 (m, 4H), 3.33 (m, 2H), 3.53-3.57(m, 1H), 3.70-3.83 (m, 4H), 4.68-4.71 (m, 1H), 4.94 (m, 1H), 5.29-5.35(m, 2H), 7.29-7.36 (m, 3H), 7.48 (d, J=2 Hz, 1H), 7.55 (s, 1H), 7.77 (d,J=8.8 Hz, 1H).

Example 33

Compounds 33B, 33C, and 33D were synthesized by employing the proceduresdescribed for Compounds 32B, 32C, and 32D using Compounds 33A, 33B, and33C in lieu of Compounds 32A, 32B, and 32C.

Compound 33B. LC-MS (ESI) m/z: 233 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ(ppm) 2.51 (s, 3H), 6.78-6.91 (m, 1H), 7.60-7.63 (m, 1H).

Compound 33C. LC-MS (ESI) m/z: 219 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ(ppm) 2.52 (s, 3H), 4.79 (s, 2H), 6.80-6.85 (m, 1H), 7.46-7.50 (m, 1H).

Compound 33D. ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 2.63 (s, 3H), 6.86-6.88(m, 1H), 7.66-7.69 (m, 1H), 10.39 (s, 1H).

A solution of Compound 33D (1 g, 4.6 mmol) and methylhydrazine (0.6 g,13.8 mmol) in 1-methylpyrrolidin-2-one (10 mL) was stirred at 20° C. for0.5 hour, and then heated at 200° C. for 2 hours in a microwave oven.The reaction mixture was cooled down to room temperature, diluted withbrine (20 mL), and extracted with diethyl ether (30 mL×2). The combinedorganic layers were washed with water (30 mL×2) and brine (30 mL), driedover anhydrous sodium sulfate, and concentrated to afford a crudeproduct. The crude was purified with flash column chromatography onsilica gel (ethyl acetate in petroleum ether, from 5% to 30% v/v) toyield Compound 33E. LC-MS (ESI) m/z: 225 [M+H]⁺; ¹H-NMR (CDCl₃, 400MHz): δ (ppm) 2.61 (s, 3H), 4.04 (s, 3H), 7.08 (d, J=8.8 Hz, 1H), 7.47(d, J=8.8 Hz, 1H), 7.95 (s, 1H).

Compound 33F was synthesized by employing the procedure described forCompound 12B using Compound 33E in lieu of Compound 12A. LC-MS (ESI)m/z: 247 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 1.43 (t, J=7.2 Hz,3H), 2.90 (s, 3H), 4.09 (s, 3H), 4.45 (q, J=6.8 Hz, 2H), 7.27 (d, J=8.0Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.20 (s, 1H).

Compounds 33G, 33H, 33I, 33J, and 33 were synthesized by employing theprocedures described for Compounds 1D, 1E, 1F, 1G, and 8 using Compounds33F, 33G, 33H, 33I, 33J, and Intermediate A in lieu of Compounds 1C, 1D,1E, 1F, 8F, and Intermediate D.

Compounds 33G. LC-MS: (ESI) m/z: 325 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ(ppm) 1.44 (t, J=6.8 Hz, 3H), 4.14 (s, 3H), 4.47 (q, J=7.2 Hz, 2H), 5.23(s, 2H), 7.42 (d, J=8.8 Hz, 1H), 7.73 (d, J=8.8 Hz, 1H), 8.32 (s, 1H).

Compounds 33H. LC-MS: (ESI) m/z: 408 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ(ppm) 1.41 (t, J=7.2 Hz, 3H), 4.13 (s, 3H), 4.45 (q, J=7.2 Hz, 2H), 5.96(s, 2H), 7.45 (t, J=8.8 Hz, 1H), 7.75-7.78 (m, 3H), 7.84-7.86 (m, 2H),8.72 (s, 1H).

Compounds 33I. LC-MS: (ESI) m/z: 260 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ(ppm) 1.47 (t, J=7.6 Hz, 3H), 4.12 (s, 3H), 4.48 (q, J=7.2 Hz, 2H), 5.36(s, 2H), 7.42 (d, J=9.2 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 8.03 (s, 1H).

Compounds 33J. LC-MS: (ESI) m/z: 232 [M+H]⁺.

Compounds 33. LC-MS (ESI) m/z: 524 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ(ppm) 0.69-0.81 (m, 4H), 2.04-2.23 (m, 4H), 3.27-3.31 (m, 2H), 3.58-3.59(m, 1H), 3.71-3.83 (m, 4H), 4.09 (s, 3H), 4.70 (d, J=10.8 Hz, 1H), 4.97(s, 1H), 5.37 (s, 2H), 7.32-7.49 (m, 5H), 8.19 (s, 1H).

Example 34

To a solution of 3-fluoro-2-methylaniline (34A) (4.0 g, 32 mmol) andNaBO₃.4H₂O (4.9 g, 32 mmol) in a mixture of acetic acid and water (20mL, 1/1 v/v) at 5-10° C. was added dropwise a solution of KI (5.3 g, 32mmol) in water (20 mL) over 30 minutes. After stirring at 20° C. for 1hour, to the mixture was added dropwise water (15 mL) over 30 minutes.The reaction mixture was filtered, washed with water (50 mL), and driedto afford Compound 34B. LC-MS (ESI) m/z: 252 [M+H]⁺; ¹H-NMR (CDCl₃, 400MHz): δ (ppm) 2.09 (s, 3H), 3.74 (s, 2H), 6.28-6.30 (m, 1H), 7.28-7.31(m, 1H).

To a solution of Compound 34B (5.0 g, 19.9 mmol) in hydrobromic acid(40%, 50 mL) at 0° C. was added dropwise a solution of sodium nitrite(1.6 g, 22.9 mmol) in water (10 mL) over 1.5 hour. After addition, themixture was stirred at 0° C. for 1.5 hour and CuBr (8.5 g, 59.7 mmol)was added, and then stirred at 0° C. for 0.5 hour and at 25° C.overnight. The reaction mixture was quenched with water (300 mL) andextracted with ethyl acetate (200 mL×3). The combined organic layerswere washed with saturated sodium hydrogen carbonate solution (100 mL)and brine (100 mL), dried over anhydrous sodium sulfate, andconcentrated to give a crude product, which was purified with flashcolumn chromatography on silica gel (ethyl acetate in petroleum ether,from 0% to 5% v/v) to yield Compound 34C. ¹H-NMR (CDCl₃, 400 MHz): δ(ppm) 2.36-2.37 (m, 3H), 7.10 (d, J=8.4 Hz, 1H), 7.41-7.45 (m, 1H).

To a solution of Compound 34C (4 g, 12.7 mmol) in dry THF (40 mL) undernitrogen at −78° C. was added n-BuLi solution (2.5 N in n-hexane, 6.1mL, 15.3 mmol). After it was stirred at −78° C. for 0.5 hour, anhydrousDMF (4.4 g, 63.7 mmol) was added. The resultant mixture was stirred at−78° C. for 0.5 hour, quenched with saturated aqueous NH₄Cl solution (20mL), and extracted with ethyl acetate (50 mL×2). The combined organiclayer was washed with brine (50 mL), dried over anhydrous sodiumsulfate, and concentrated to give a crude product, which was purifiedwith flash column chromatography on silica gel (ethyl acetate inpetroleum ether, 5% v/v) to afford Compound 34D. ¹H-NMR (CDCl₃, 400MHz): δ (ppm) 2.40-2.41 (m, 3H), 7.47-7.49 (m, 1H), 7.56-7.58 (m, 1H),10.32 (s, 1H).

A solution of Compound 34D (1 g, 4.6 mmol) and hydrazine monohydrate(1.1 g, 23 mmol) in 1-methylpyrrolidin-2-one (10 mL) was stirred at 20°C. for 0.5 hour, and then heated at 200° C. for 1 hour in a microwaveoven. The reaction mixture was cooled down to room temperature, dilutedwith brine (20 mL), and extracted with diethyl ether (30 mL×2). Thecombined organic layers were washed with water (30 mL×2) and brine (30mL), dried over anhydrous sodium sulfate, and concentrated to give acrude product, which was purified with flash column chromatography onsilica gel (ethyl acetate in petroleum ether, from 5% to 30% v/v) toyield Compound 34E. LC-MS (ESI) m/z: 211 [M+H]⁺; ¹H-NMR (CDCl₃, 400MHz): δ (ppm) 2.61 (s, 3H), 7.33 (d, J=8.4 Hz, 1H), 7.45 (d, J=8.4 Hz,1H), 8.06 (s, 1H), 10.36 (s, 1H).

To an ice-cooled solution of Compound 34E (0.2 g, 0.9 mmol) in DMF (5mL) was added sodium hydride (60% in mineral, 57 mg, 1.4 mmol). Afterthe mixture was stirred at room temperature for 30 minutes, iodomethane(0.67 g, 4.5 mmol) was added. The reaction mixture was stirred at roomtemperature for 1 hour, quenched with ammonium chloride solution (10mL), and extracted with ethyl acetate (40 mL×3). The combined organiclayers were washed with water (50 mL×4) and brine (50 mL), dried overanhydrous sodium sulfate, and concentrated to give a crude product,which was purified with flash column chromatography on silica gel (ethylacetate in petroleum ether, from 0% to 40% v/v) to afford Compound 34Fand Compound 34G. Compound 34F: LC-MS (ESI) m/z: 225 [M+H]⁺; ¹H-NMR(CDCl₃, 400 MHz): δ (ppm) 2.85 (s, 3H), 4.32 (s, 3H), 7.28 (d, J=8.4 Hz,1H), 7.36 (d, J=8.4 Hz, 1H), 7.87 (s, 1H). Compound 34G: LC-MS (ESI)m/z: 225 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 2.67 (s, 3H), 4.20 (s,3H), 7.19 (d, J=8.8 Hz, 1H), 7.33 (d, J=8.8 Hz, 1H), 7.84 (s, 1H).

Compound 34H is synthesized by employing the procedure described forCompound 12B using Compound 34F in lieu of Compound 12A. LC-MS (ESI)m/z: 247 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 1.43 (t, J=7.2 Hz,3H), 2.98 (s, 3H), 4.42 (s, 3H), 4.46 (q, J=6.8 Hz, 2H), 7.31 (d, J=8.4Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.98 (s, 1H).

Compounds 34I, 34J, 34K, 34L, and 34 were-synthesized by employing theprocedures described for Compounds 1D, 1E, 1F, 1G, and 8 using Compounds34H, 34I, 34J, 34K, 34L, and Intermediate A in lieu of Compounds 1C, 1D,1E, 1F, 8F, and Intermediate D.

Compounds 34I. LC-MS: (ESI) m/z: 325 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ(ppm) 1.43 (t, J=7.2 Hz, 3H), 4.47 (q, J=7.2 Hz, 2H), 4.59 (s, 3H), 5.32(s, 2H), 7.39 (d, J=8.4 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 8.06 (s, 1H).

Compounds 34J. LC-MS: (ESI) m/z: 408 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ(ppm) 1.33 (t, J=7.2 Hz, 3H), 4.33 (q, J=7.6 Hz, 2H), 4.63 (s, 3H), 5.88(s, 2H), 7.25-7.27 (m, 1H), 7.70-7.78 (m, 4H), 7.85-7.87 (m, 1H), 8.11(s, 1H).

Compounds 34K. LC-MS: (ESI) m/z: 260 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ(ppm) 1.46 (t, J=6.8 Hz, 3H), 4.27 (s, 3H), 4.48 (q, J=7.2 Hz, 2H), 5.60(s, 2H), 7.58 (d, J=8.4 Hz, 1H), 7.76 (d, J=8.4 Hz, 1H), 8.01 (s, 1H).

Compounds 34L. LC-MS: (ESI) m/z: 232 [M+H]⁺.

Compounds 34. LC-MS (ESI) m/z: 524 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ(ppm) 0.69-0.82 (m, 4H), 2.05-2.23 (m, 4H), 3.21-3.31 (m, 2H), 3.57-3.61(m, 1H), 3.71-3.84 (m, 4H), 4.26 (s, 3H), 4.73 (d, J=10.8 Hz, 1H), 4.97(s, 1H), 5.6 (q, J=13.6 Hz, 2H), 6.9 (d, J=8.4 Hz, 1H), 7.36-7.37 (m,2H), 7.49 (s, 1H), 7.65 (d, J=8.8 Hz, 1H), 8.04 (s, 1H).

Example 35

Compound 35A is synthesized by employing the procedure described forCompound 12B using Compound 34G in lieu of Compound 12A.

Compounds 35B, 35C, 35D, 35E, and 35 are synthesized by employing theprocedures described for Compounds 1D, 1E, 1F, 1G, and 1 using Compounds35A, 35B, 35C, 35D, and 35E in lieu of Compounds 1C, 1D, 1E, 1F, and 1G.

Example 36

To a solution of ethyl cyanoacetate (11.53 g, 102 mmol) and potassiumhydroxide (5.7 g, 102 mmol) in DMF (87 mL) was added nitroquinoline(36A, 5.96 g, 34 mmol) and the reaction mixture was stirred at 25° C.for 22 hours. The mixture was concentrated in vacuo. The residue wastreated with 10% hydrochloric acid (100 mL) and heated at reflux for 3hours. The reaction mixture was basified with 10% aqueous sodiumhydroxide and extracted with chloroform and methanol (20:1, 100 mL×3).The combined organic layer was washed with brine, dried over sodiumsulfate, filtered, and evaporated to give a crude product, which waspurified by flash chromatography on silica gel (methanol indichloromethane, 5% to 10% v/v) to furnish Compound 36B. LC-MS (ESI)m/z: 170 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 6.90 (s, 2H), 7.23(d, J=9.6 Hz, 1H), 7.48-7.51 (m, 1H), 7.88 (d, J=9.6 Hz, 1H), 8.01 (d,J=8.8 Hz, 1H), 8.58 (m, 1H).

To a solution of Compound 36B (5.07 g, 30 mmol) in acetonitrile (150 mL)under nitrogen was added cupper bromide (8 g, 36 mmol) and the reactionmixture was stirred at room temperature for 10 minutes. To the mixturewas added tert-butyl nitrite (4.7 mL, 39 mmol) and the reaction mixturewas heated at 60° C. for 15 hours. Hydrochloric acid (1 N, 100 mL) wasadded to the mixture and the reaction mixture was stirred for another 4hours. The mixture was basified to pH 6 with solid NaHCO₃ and extractedwith ethyl acetate (100 mL×3). The combined organic layers were washedwith saturated NH₄Cl solution (100 mL) and brine (100 mL), dried oversodium sulfate, and evaporated to give a crude Compound 36C. LC-MS (ESI)m/z: 233 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 7.63-7.66 (m, 1H),7.94 (d, J=8.8 Hz, 1H), 8.21 (d, J=8.8 Hz, 1H), 8.52 (d, J=8.8 Hz, 1H),9.06 (s, 1H).

To a solution of Compound 36C (2.4 g, 10 mmol) in toluene (80 mL) at −5°C. under nitrogen was slowly added a solution of diisobutylaluminiumhydride (25% in toluene, 10 mL, 17 mmol) and the reaction mixture wasstirred at 10° C. for 3 hours. After the reaction mixture was cooled to−5° C., the reaction mixture was quenched with a solution of 5% sulfuricacid and stirred at room temperature for 1 hour. The mixture wasbasified with saturated NaHCO₃ solution and extracted with ethyl acetate(100 mL×3). The combined organic layers were washed with brine (100 mL),dried over sodium sulfate, and evaporated to give a crude product, whichwas purified by flash chromatography on silica gel (methanol indichloromethane, 5% to 10% v/v) to furnish Compound 36D. LC-MS (ESI)m/z: 236 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 7.56-7.59 (m, 1H),7.94 (d, J=8.8 Hz, 1H), 8.16 (d, J=8.8 Hz, 1H), 8.97-8.98 (m, 1H), 9.46(d, J=8.8 Hz, 1H), 10.71 (s, 1H).

Compound 36E was synthesized by employing the procedure described forCompound 22D using Compound 36D in lieu of Compound 22C, which was usedwithout further purification. LC-MS (ESI) m/z: 238 [M+H]⁺.

To a solution of Compound 36E (2.17 g, 9.2 mmol) in CH₃CN (150 mL) at 0°C. was added NaI (6.9 mg, 46 mmol) and TMSCl (4 mL, 46 mmol) and thereaction mixture was stirred at 50° C. for 24 hours. The reactionmixture was evaporated under vacuum to give a crude product, which waspurified by flash chromatography on silica gel (methanol indichloromethane, 0% to 20% v/v) to furnish Compound 36F, which was usedwithout further purification. LC-MS (ESI) m/z: 348 [M+H]⁺.

Compound 36G was synthesized by employing the procedure described forCompound 20E using Compound 36F in lieu of Compound 20D. LC-MS (ESI)m/z: 222 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 2.77 (s, 3H),7.43-7.46 (m, 1H), 7.83 (s, 2H), 8.37 (d, J, =8.8 Hz, J₂=1.6 Hz, 1H),8.91 (d, J=4.4 Hz, J₂=1.6 Hz, 1H).

Compound 36H was synthesized by employing the procedure described forCompound 12B using Compound 36G in lieu of Compound 12A. LC-MS (ESI)m/z: 244 [M+H]⁺; H-NMR (CDCl₃, 400 MHz): δ (ppm) 1.44 (t, J=7.6 Hz, 3H),2.89 (s, 3H), 4.44-4.50 (m, 2H), 7.52-7.55 (m, 1H), 7.87 (d, J=8.8 Hz,1H), 8.05 (d, J=8.4 Hz, 1H), 8.56 (d, J=8.8 Hz, 1H), 9.02-9.03 (m, 1H).

Compounds 36I, 36J, 36K, 36L, and 36 were synthesized by employing theprocedures described for Compounds 1D, 1E, 1F, 1G, and 1 using Compounds36H, 36I, 36J, 36K, 36L, and Intermediate A in lieu of Compounds 1C, 1D,1E, 1F, 8F, and Intermediate D.

Compounds 36I. LC-MS (ESI) m/z: 322 [M+H]⁺.

Compounds 36J. LC-MS (ESI) m/z: 405 [M+H]⁺.

Compounds 36K. LC-MS (ESI) m/z: 257 [M+H]⁺.

Compounds 36L. LC-MS (ESI) m/z: 229 [M+H]⁺.

Compounds 36. LC-MS (ESI) m/z: 521 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ(ppm) 0.68-0.84 (m, 4H), 1.29-1.32 (m, 2H), 2.06-2.21 (m, 4H), 2.87-3.00(m, 1H), 3.19-3.27 (m, 2H), 3.57-3.61 (m, 1H), 3.70-3.86 (m, 4H),4.73-4.75 (m, 1H), 4.98 (s, 1H), 5.54-5.63 (m, 2H), 7.34-7.40 (m, 2H),7.50 (s, 1H), 7.65-7.72 (m, 2H), 7.98 (d, J=8.8 Hz, 1H), 8.63 (d, J=8.4Hz, 1H), 9.00 (s, 1H).

Example 37

To a solution of 2-(thiophen-3-yl)acetic acid (37A, 1.42 g, 10 mmol) inmethanol (25 mL) was added dropwise concentrated H₂SO₄ (0.5 mL). Thereaction mixture was heated to reflux for overnight and then cooled downto room temperature. After removal of solvent, the residue waspartitioned between dichloromethane (20 mL) and water (20 mL). Theorganic layer was washed with saturated aqueous NaHCO₃ solution (20 mL)and water (20 mL) and brine (20 mL), dried over anhydrous sodiumsulfate, and concentrated to afford Compound 37B. LC-MS (ESI) m/z: 157[M+H]⁺.

To a solution of Compound 37B (1.6 g, 10 mmol) and AcCl (1.0 g, 12 mmol)in dichloromethane (40 mL) under nitrogen at room temperature was slowlyadded SnCl₄ (7.8 g, 30 mmol) and the reaction mixture was stirred atroom temperature overnight. The reaction mixture was quenched withice-water (100 mL) and extracted with ethyl acetate (50 mL×3). Thecombined organic layers were washed with saturated aqueous NaHCO₃solution (30 mL) and water (30 mL) and brine (30 mL), dried overanhydrous sodium sulfate, and concentrated to give a crude product,which was purified with flash column chromatography on silica gel (ethylacetate in petroleum ether, from 10% to 50% v/v) to furnish Compound37C. LC-MS (ESI) m/z: 199 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 2.54(s, 3H), 3.71 (s, 3H), 4.07 (s, 2H), 7.06 (d, J=4.8 Hz, 1H), 7.46 (d,J=4.8 Hz, 1H).

To a solution of Compound 37C (0.75 g, 3.55 mmol) in THF/MeOH (9 mL/1mL) was added aqueous KOH solution (2 M, 5 mL). The mixture was stirredat room temperature for about 2 hours until the reaction was completedas shown by thin layer chromatography. The reaction mixture wasacidified to pH 2 with diluted aqueous HCl solution (1.0 N, 40 mL) andextracted with ethyl acetate (30 mL×2). The combined organic layers werewashed with water (100 mL) and brine (100 mL), dried over anhydroussodium sulfate, and concentrated to yield Compound 37D. LC-MS (ESI) m/z:185 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 2.50 (s, 3H), 3.94 (s,2H), 7.14 (d, J=4.8 Hz, 1H), 7.82 (d, J=4.8 Hz, 1H), 12.32 (s, 1H).

A mixture of Compound 37D (1.84 g, 10 mmol) and Ac₂O (30 mL) was heatedto reflux for 4 hours. After removal of the reagent, the residue wasdissolved in ether (100 mL), washed with water (100 mL) and brine (100mL), dried over anhydrous sodium sulfate, and evaporated to giveCompound 37E. LC-MS (ESI) m/z: 167 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ(ppm) 2.50 (s, 3H), 6.26 (s, 1H), 6.78 (d, J=5.6 Hz, 1H), 7.53 (d, J=5.6Hz, 1H).

A mixture of Compound 37E (1.66 g, 10 mmol) and methyl propiolate (3.2g, 38 mmol) in PhBr (50 mL) was refluxed under nitrogen for 4 hours.After evaporation, the residue was purified with flash columnchromatography on silica gel (ethyl acetate in petroleum ether, from 10%to 50% v/v) to furnish Compound 37F. LC-MS (ESI) m/z: 207 [M+H]⁺.

To a solution of Compound 37F (200 mg, 1 mmol) in THF (10 mL) was addedLAH (50 mg, 1.3 mmol) and the reaction mixture was stirred at roomtemperature for 2 hours. The reaction mixture was quenched withNa₂SO₄.10H₂O, filtered, and concentrated to give a crude Compound 37G.LC-MS (ESI) m/z: 179 [M+H]⁺.

Compound 37H was synthesized by employing the procedure described forCompound 32D using Compound 37G in lieu of Compound 32C. LC-MS (ESI)m/z: 177 [M+H]⁺.

To a solution of diisopropylamine (0.408 mL, 2.92 mmol) in anhydrous THF(10 mL) was added a solution of n-BuLi in n-hexane (2.5 M, 1.16 mL, 2.92mmol) at −60° C. under nitrogen and stirred at −60° C. for 1 hour. To itwas added dropwise a solution of Compound 37F (548 mg, 2.65 mmol) inanhydrous THF (3 mL). After the mixture was stirred at −60° C. for 1hour, a solution of CCl₄ (1.64 g, 10.6 mmol) in anhydrous THF (4 mL) wasadded in one portion. The reaction mixture was stirred at −60° C. for 2hours, quenched with saturated annonium chloride solution (26 mL), andextracted with ethyl acetate (50 mL×2). The combined organic layers waswashed with water (50 mL) and brine (50 mL), dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas purified with flash column chromatography on silica gel (ethylacetate in petroleum ether, from 10% to 50% v/v) to furnish Compound37G. LC-MS (ESI) m/z: 241 [M+H]⁺, ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 2.78(s, 3H), 3.75 (s, 3H), 7.20 (s, 1H), 7.26 (d, J=8.8 Hz, 1H), 7.92 (d,J=8.8 Hz, 1H).

To a solution of Compound 37G (240 mg, 1 mmol) in anhydrous THF (10 mL)was added LiAlH₄ (50 mg, 1.3 mmol). The reaction mixture was stirred atroom temperature for 2 hours, quenched with Na₂SO₄.10H₂O, and filtered.The filtrate was concentrated to give a crude Compound 37H. LC-MS (ESI)m/z: 213 [M+H]⁺.

To a solution of Compound 37H (212 mg, 1 mmol) in dichloromethane (10mL) was added Dess-Martin peroidinane (551 mg, 1.3 mmol) and stirred atroom temperature overnight. The reaction mixture was quenched withsaturated aqueous Na₂S₂O₃ solution (20 mL), followed by addition ofdichloromethane (50 mL) and water (30 mL). The organic layer wasseparated, washed with brine (30 mL), dried over anhydrous sodiumsulfate, filtered, and concentrated to give a crude product, which waspurified with flash column chromatography on silica gel (ethyl acetatein petroleum ether, from 10% to 50% v/v) to furnish Compound 371. LC-MS(ESI) m/z: 211 [M+H]⁺.

To a solution of Compound 371 (211 mg, 1 mmol) and NaCN (103 mg, 1.5mmol) in methanol (10 mL) was dropped AcOH (0.5 mL) and stirred at roomtemperature overnight. The reaction mixture was poured into water (20mL) and extracted with ethyl acetate (20 mL×2). The combined organiclayers was washed with water (20 mL) and brine (30 mL), dried overanhydrous sodium sulfate, filtered, and concentrated to give a crudeproduct, which was purified with flash column chromatography on silicagel (ethyl acetate in petroleum ether, from 10% to 50% v/v) to affordCompound 37J. LC-MS (ESI) m/z: 238 [M+H]⁺.

To a mixture of Compound 37J (237 mg, 1 mmol) in anhydrous ethanol (10mL) was bubbled with a stream of HCl gas at 0° C. for 6 hours. Themixture was stirred at 20° C. for 16 hours. After removal of most ofsolvent, the residue was diluted with ice water (100 mL) and stirred at20° C. for 1 hour. The mixture was extracted with dichloromethane (100mL×3). The combined organic layers was washed with water (200 mL) andbrine (200 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated to give a crude product, which was purified with flashcolumn chromatography on silica gel (ethyl acetate in petroleum, from 0%to 30% v/v) to yield Compound 37K. LC-MS (ESI) m/z: 285 [M+H]⁺.

Compound 37L was synthesized by employing the procedure described forCompound 371 using Compound 37K in lieu of Compound 37H. LC-MS (ESI)m/z: 283 [M+H]⁺.

Compounds 37M, 37N, 370, 37P, and 37 were synthesized by employing theprocedures described for Compounds 1D, 1E, 1F, 1G, and 8 using Compounds37L, 37M, 37N, 370, 37P, and Intermediate A in lieu of Compounds 1C, 1D,1E, 1F, 8F, and Intermediate D.

Compounds 37M. LC-MS (ESI) m/z: 361 [M+H]⁺.

Compounds 37N. LC-MS (ESI) m/z: 444 [M+H]⁺.

Compounds 37O. LC-MS (ESI) m/z: 296 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ(ppm) 1.38 (t, J=6.8 Hz, 3H), 1.43 (q, J=6.8 Hz, 2H), 5.12 (s, 2H), 7.20(s, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H).

Compounds 37P. LC-MS (ESI) m/z: 268 [M+H]⁺.

Compounds 37. LC-MS (ESI) m/z: 560 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ(ppm) 0.67-0.82 (m, 4H), 1.71-2.04 (m, 4H), 3.14-3.21 (m, 2H), 3.51-3.54(m, 4H), 3.88-3.89 (m, 1H), 4.53-4.55 (m, 1H), 4.80-4.81 (m, 1H),5.17-5.32 (m, 2H), 6.01-6.03 (m, 1H), 7.31-7.37 (m, 2H), 7.42 (s, 1H),7.54 (d, J=8.8 Hz, 1H), 7.72 (s, 1H), 7.81 (d, J=8.8 Hz, 1H), 8.42-8.44(m, 1H), 9.26 (brs, 1H).

Example 38

To a solution of Compound 38A (2 g, 10 mmol) in THF (20 mL) and water (5mL) was added sodium bicarbonate (5.1 g, 60 mmol) and Boc₂O (4.4 g, 20mmol) and the reaction mixture was stirred at room temperatureovernight. The reaction mixture was quenched with water (50 mL),extracted with ethyl acetate (50 mL×2), washed with water (50 mL×2) andbrine (50 mL), dried over anhydrous sodium sulfate, and concentrated tofurnish Compound 38B, which was used without further purification. LC-MS(ESI) m/z: 244 [M-55]⁺.

Compound 38C was synthesized by employing the procedure described forCompound 1B using Intermediate 38B in lieu of Intermediate 1A. LC-MS(ESI) m/z: 316 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 1.43 (s, 9H),2.86 (t, J=6.8 Hz, 2H), 3.41-3.43 (m, 2H), 7.09-7.18 (m, 3H), 7.36-7.41(m, 3H), 7.51-7.55 (m, 2H).

To a solution of Compound 38C (2.5 g, 7.9 mmol) in dichloromethane (20mL) was added a solution of hydrogen chloride in 1,4-dioxane (4 M, 4 mL)and the reaction mixture was stirred at room temperature overnight. Thereaction mixture was treated with saturated aqueous of sodiumbicarbonate (50 mL), extracted with dichloromethane (50 mL×2), washedwith brine (50 mL), dried over anhydrous sodium sulfate, andconcentrated to furnish Compound 38D. LC-MS (ESI) m/z: 216 [M+H]⁺.

To a solution of diethyl oxalate (876 mg, 6.0 mmol) in toluene (10 mL)was added Compound 38D (860 mg, 4.0 mmol) dropwise. The mixture wasstirred at room temperature for 45 min and 60° C. for 2 h. The resultingmixture was concentrated. The residue was purified with prep-TLC (ethylacetate in petroleum ether, 30% v/v) to give Compound 38E. LC-MS (ESI)m/z: 316 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 1.36 (t, J=6.8 Hz,3H), 2.93 (q, J=6.8 Hz, 2H), 3.65 (q, J=6.8 Hz, 2H), 4.33 (q, J=6.8 Hz,2H), 7.10-7.19 (m, 4H), 7.37-7.55 (m, 5H).

To a solution of Compound 38E (315 mg, 1.0 mmol) in POCl₃ (459 mg, 3.0mmol) was added zinc chloride (272 mg, 2.0 mmol). The reaction mixturewas stirred under nitrogen atmosphere at 90° C. for 2 hours. To themixture at 60° C. was added toluene (2 mL). After the mixture was cooleddown to a room temperature, to it was added ethanol (1 mL), water (4mL), aqueous sodium hydroxide solution (25%, 8 mL), and ethyl acetate (4mL). The mixture was filtered with Celite and washed with ethyl acetate(6 mL). The organic layer was separated and the aqueous layer wasextracted with ethyl acetate (10 mL). The organic layers were combined,dried over anhydrous sodium sulfate, and concentrated to furnishCompound 38F. LC-MS (ESI) m/z: 298 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ(ppm) 1.34 (t, J=7.2 Hz, 3H), 2.93 (t, J=8.0 Hz, 2H), 3.86 (t, J=8.0 Hz,2H), 4.40 (q, J=7.2 Hz, 2H), 7.33-7.37 (m, 2H), 7.72-7.75 (m, 3H),7.80-7.84 (m, 2H).

Compound 38G was synthesized by employing the procedure described forCompound 1G using Compound 38F in lieu of Compound 1F. LC-MS (ESI) in/z:270 [M+H]⁺.

Compound 38 was synthesized by employing the procedure described forCompound 8 using Compound 38G in lieu of Compound 8F. LC-MS (ESI) m/z:546 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ (ppm) 0.74-0.82 (m, 4H),2.09-2.22 (m, 4H), 3.00-3.03 (m, 2H), 3.21-3.28 (m, 2H), 3.51-3.54 (m,1H), 3.77-3.94 (m, 5H), 4.82-4.85 (m, 2H), 5.00 (s, 1H), 6.32 (d, J=8.4Hz, 1H), 7.21-7.27 (m, 4H), 7.36-7.42 (m, 2H), 7.60 (s, 1H), 7.71-7.74(m, 2H).

Example 39

Compound 39 was synthesized by employing the procedure described forCompound 8 using Compound 38G and Intermediate H in lieu of Compound 8Fand Intermediate D. LC-MS (ESI) m/z: 576 [M+H]⁺. ¹H-NMR (CD₃OD, 400MHz): δ (ppm) 0.73-0.84 (m, 4H), 2.10-2.22 (m, 4H), 2.87-3.09 (m, 5H),3.41-3.95 (m, 7H), 4.14-4.21 (m, 1H), 5.17 (d, J=4.4 Hz, 1H), 5.53-5.55(m, 1H), 6.03 (s, 1H), 7.24-7.33 (m, 4H), 7.47 (s, 2H), 5.58-5.59 (m,2H), 7.71-7.74 (m, 2H).

Example 40

Compound 40 was synthesized by employing the procedure described forCompound 8 using Compound 38G and Intermediate G in lieu of Compound 8Fand Intermediate D. LC-MS (ESI) m/z: 514 [M+H]; ¹H-NMR (CD₃OD, 400 MHz):δ (ppm) 0.68-0.79 (m, 4H), 2.48-2.70 (m, 2H), 2.99 (t, J=8.0 Hz, 2H),3.57-3.65 (m, 2H), 3.76-3.78 (m, 1H), 3.94-3.99 (m, 2H), 4.18-4.42 (m,4H), 4.63-4.66 (m, 1H), 4.99 (d, J=3.2 Hz, 1H), 6.64 (d, J=8.0 Hz, 1H),7.05 (d, J=8.8 Hz, 2H), 7.25 (t, J=8.8 Hz, 2H), 7.38 (t, J=8.4 Hz, 3H),7.58 (s, 1H), 7.69-7.73 (m, 2H).

Example 41

Compound 41B was synthesized by employing the procedure described forCompound 1B using Intermediate 41A in lieu of Intermediate 1A. LC-MS(ESI) m/z: 212 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 3.74 (s, 2H),7.07 (t, J=8.8 Hz, 2H), 7.18-7.24 (m, 1H), 7.35-7.39 (m, 1H), 7.42-7.48(m, 4H).

To a vial containing dried CeCl₃ (9.3 g, 38 mmol), which was purged 3times with nitrogen, was added anhydrous THF (50 mL) via a syringe. Tothe mixture at −78° C. was added dropwise a solution of MeLi in THF (12mL, 37 mmol). After the mixture was stirred at −78° C. for 1 h., asolution of Compound 41B (2 g, 9.5 mmol) in THF (10 mL) was addeddropwise. The mixture was stirred at −78° C. for 1 h and at roomtemperature for 1 h. The reaction mixture was quenched with severaldrops of aq. ammonium chloride solution and basified with ammonia (10mL). The mixture was filtered and washed with ethyl acetate (50 mL). Thefiltrate was extracted with ethyl acetate (50 mL×2), washed with brine(50 mL), dried over anhydrous sodium sulfate, concentrated, and purifiedwith flash column chromatography on silica gel (ethyl acetate inpetroleum ether, 10%, v/v) to furnish Compound 41C. LC-MS (ESI) m/z: 229[M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 2.19 (s, 3H), 3.76 (s, 2H),7.12 (t, J=7.2 Hz, 2H), 7.18 (d, J=5.6 Hz, 1H), 7.37-7.38 (m, 1H),7.40-7.41 (m, 1H), 7.44-7.45 (m, 1H), 7.51-7.54 (m, 2H).

To a solution of Compound 41C (1.5 g, 6.5 mmol) in THF (20 mL) undernitrogen at −10° C. was added a solution of CH₃MgBr in THF (1 M, 13 mL,13.1 mmol). The mixture was stirred at room temperature for 2 h. Thereaction mixture was treated with sat. ammonium chloride solution andextracted with ethyl acetate (50 mL×2), washed with water (50 mL×2) andbrine (50 mL), dried over anhydrous sodium sulfate, concentrated, andpurified with flash column chromatography on silica gel (ethyl acetatein petroleum ether, 10%, v/v) to furnish Compound 41D. LC-MS (ESI) m/z:227 [M-OH]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 1.27 (s, 6H), 2.83 (s,2H), 7.12 (t, J=8.8 Hz, 2H), 7.19-7.21 (m, 1H), 7.36-7.39 (m, 2H),7.42-7.44 (m, 1H), 7.52-7.56 (m, 2H).

To a mixture of Compound 41D (700 mg, 2.86 mmol) and ClCH₂CN (645 mg,8.60 mmol) was added AcOH (516 mg, 8.6 mmol). The mixture was cooled to0-3° C. and concentrated H₂SO₄ (843 mg, 8.6 mmol) was added dropwise ata rate of keeping the temperature below 10° C. The reaction mixture wasstirred for 5 h. and allowed to reach room temperature. It was pouredinto ice water, extracted with ethyl acetate (50 mL×2), washed with sat.sodium bicarbonate (50 mL) and brine (50 mL), dried over anhydroussodium sulfate, and concentrated to afford Compound 41E. LC-MS (ESI)m/z: 320 [M+H]⁺.

A solution of Compound 41E (800 mg, 2.5 mmol) and thiourea (229 mg, 3mmol) in ethanol (5 mL) and AcOH (1 mL) was refluxed for 10 h. It wastreated with water and 20% NaOH, extracted with dichloromethane (50mL×2), washed with sodium bicarbonate (50 mL) and brine (50 mL), driedover anhydrous sodium sulfate, concentrated, and furnish Compound 41F.LC-MS (ESI) m/z: 244 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 1.09 (s,6H), 2.66 (s, 2H), 7.03-7.11 (m, 3H), 7.28-7.36 (m, 3H), 7.45-7.48 (m,2H).

To a solution of Compound 41F (330 mg, 1.36 mmol) in THF (15 mL) at 0°C. was added triethylamine (411 mg, 4.07 mmol) and ethyl2-chloro-2-oxoacetate (277 mg, 2.04 mmol) and was stirred at roomtemperature for 1.5 h. The mixture was treated with water (50 mL),extracted with ethyl acetate (50 mL×2), washed with sat. sodiumbicarbonate (50 mL) and brine (50 mL), dried over anhydrous sodiumsulfate, concentrated, and purified with flash column chromatography onsilica gel (ethyl acetate in petroleum ether, 10%, v/v) to furnishCompound 41G. LC-MS (ESI) m/z: 344 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ(ppm) 1.35 (t, J=7.2 Hz, 3H), 1.43 (s, 6H), 3.11 (s, 2H), 4.30 (q, J=7.2Hz, 2H), 7.09-7.13 (m, 3H), 7.29 (s, 1H), 7.34-7.38 (m, ¹H), 7.41-7.43(m, 1H), 7.49-7.53 (m, 2H).

Compound 41H was synthesized by employing the procedure described forCompound 38F using Compound 41G in lieu of Compound 38E. LC-MS (ESI)m/z: 326 [M+H]⁺.

Compound 41I was synthesized by employing the procedure described forCompound 1G using Compound 41H in lieu of Compound 1F. LC-MS (ESI) m/z:298 [M+H]⁺.

Compound 41 was synthesized by employing the procedure described forCompound 8 using Compound 41I and Intermediate A in lieu of Compound 8Fand Intermediate D. LC-MS (ESI) m/z: 590 [M+H]⁺; ¹H-NMR (CD₃OD, 400MHz): δ (ppm) 0.73-0.83 (m, 4H), 1.29 (s, 3H), 1.37 (s, 3H), 2.11-2.24(m, 4H), 2.87-2.96 (m, 2H), 3.27 (s, 2H), 3.49-3.53 (m, 1H), 3.78-3.89(m, 4H), 4.82-4.85 (m, 1H), 4.99 (d, J=2.4 Hz, 1H), 6.54 (d, J=8.0 Hz,1H), 7.24 (t, J=8.8 Hz, 2H), 7.29-7.31 (m, 1H), 7.39 (s, 2H), 7.47-7.50(m, 2H), 7.70-7.74 (m, 2H).

Example 42

Compound 42B was synthesized by employing the procedure described forCompound 1B using Intermediate 42A in lieu of Intermediate 1A. LC-MS(ESI) m/z: 199 [M-OH]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 1.49 (t, J=5.2Hz, 1H), 2.93 (t, J=6.8 Hz, 1H), 3.88-3.93 (m, 2H), 7.12 (t, J=8.8 Hz,2H), 7.21 (d, J=7.2 Hz, 2H), 7.36-7.42 (m, 3H), 7.52-7.55 (m, 2H).

A mixture of Compound 42B (1 g, 4.6 mmol) and 2-oxoacetic acid hydrate(468 mg, 5.1 mmol) in CF₃COOH (5 mL) was stirred at reflux for 24 h. Theresulting mixture was concentrated to remove CF₃COOH, adjusted to pH 8with NH₄OH, and extracted with ethyl acetate (50 mL×2). The aqueousphase was adjusted to pH 2 with diluted HCl solution and extracted withethyl acetate (50 mL×2). The organic layer was concentrated, washed withether, and filtered to furnish Compound 42C. LC-MS (ESI) m/z: 227[M-COOH]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 2.79-2.93 (m, 2H),3.91-3.97 (m, 1H), 4.12-4.18 (m, 1H), 5.32 (s, 1H), 7.29 (t, J=9.2 Hz,2H), 7.41-7.49 (m, 3H), 7.68-7.71 (m, 2H), 13.01 (s, 1H).

Compound 42 was synthesized by employing the procedure described forCompound 8 using Compound 42C and Intermediate A in lieu of Compound 8Fand Intermediate D. LC-MS (ESI) m/z: 565 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400MHz): δ (ppm) 0.44-0.79 (m, 4H), 1.82-2.09 (m, 4H), 2.78-3.14 (m, 4H),3.37-3.56 (m, 6H), 4.08-4.11 (m, 1H), 4.42-4.45 (m, 1H), 4.74-4.87 (m,1H), 5.15 (t, J=7.2 Hz, 1H), 6.92-7.17 (m, 2H), 7.23-7.27 (m, 3H),7.34-7.48 (m, 3H), 7.56-8.06 (m, 3H).

Example 43

To a mixture of Compound 43A (25 g, 0.145 mol) and K₂CO₃ (26 g, 0.188mol) in dry DMF (150 mL) at 0° C. was added ethyl 2-mercaptoacetate (16mL, 0.146 mmol) in small portions over 1 h. The mixture was slowlywarmed to room temperature and stirred for 16 h. The reaction mixturewas heated at 80° C. for 24 h. After it was cooled, to it was addedwater (300 mL). The resulting mixture was stirred at room temperaturefor 30 min. and filtered. The filtrate was diluted with ethyl acetate(200 mL), washed with water (100 mL) and brine (100 mL), dried overanhydrous sodium sulfate, concentrated, and offer the Compound 43B.LC-MS (ESI) m/z: 255 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 1.41 (t,J=7.6 Hz, 3H), 2.74 (s, 3H), 4.39 (q, J=6.8 Hz, 2H), 7.35-7.38 (m, 1H),7.72 (d, J=8.4 Hz, 1H), 7.78 (d, J=1.6 Hz, 1H).

To a solution of Compound 43B (35 g, 0.14 mol) in THF (100 mL) was addeda solution of LiOH.H₂O (6.9 g, 0.17 mol) in water (10 mL). The resultingmixture was stirred at room temperature for 12 h. and its pH wasadjusted to about 1 with diluted HCl solution. The mixture was extractedwith ethyl acetate (100 mL×2). The organic layer was concentrated,filtered, and washed with petroleum ether to afford Compound 43C. LC-MS(ESI) m/z: 225 [M−H]⁺; ¹H-NMR (DMSO, 400 MHz): δ (ppm) 2.70 (s, 3H),7.48-7.51 (m, 1H), 7.94 (d, J=8.4 Hz, 1H), 8.16 (d, J=1.6 Hz, 1H).

A suspension of Compound 43C (25 g, 0.11 mol) and Cu powder (3.5 g, 55mmol) in quinoline (100 mL) was stirred at 210° C. for 4 h. After thereaction mixture was cooled to room temperature, it was filtered andwashed with ethyl acetate (100 mL×3) and diluted HCl (100 mL×3) andbrine (100 mL), dried over anhydrous sodium sulfate, concentrated, andpurified with flash column chromatography on silica gel (petroleum ether100%, v/v) to furnish Compound 43D. ¹H-NMR (CDCl₃, 400 MHz): δ (ppm)2.39 (s, 3H), 7.03 (s, 1H), 7.31-7.34 (m, 1H), 7.58 (d, J=8.8 Hz, 1H),7.79 (d, J=2.0 Hz, 1H).

To a solution of Compound 43D (3 g, 16 mmol) in CCl₄ (20 mL) was addedNBS (3.2 g, 18 mmol) and BPO (398 mg, 1.6 mmol). The mixture was heatedto reflux for 3 h., cooled down to room temperature, and extracted withdichloromethane (50 mL×3). The extracts were washed with water (50 mL×2)and brine (50 mL), dried over anhydrous sodium sulfate, concentrated,and purified with flash column chromatography on silica gel (ethylacetate in petroleum ether, 10%, v/v) to furnish Compound 43E. ¹H-NMR(CDCl₃, 400 MHz): δ (ppm) 4.71 (s, 2H), 7.41-7.43 (m, 1H), 7.49 (s, 1H),7.79-7.84 (m, 2H).

To a solution of Compound 43E (3.4 g, 13 mmol) in DMF (10 mL) was addedNaCN (1.3 g, 26 mmol) in water (5 mL). The resulting mixture was stirredat room temperature for 2 h. The reaction was quenched with water (50mL), extracted with ethyl acetate (50 mL×3), washed with water (50 mL×3)and brine (50 mL), dried over anhydrous sodium sulfate, concentrated,and purified with flash column chromatography on silica gel (ethylacetate in petroleum ether, 10%, v/v) to furnish Compound 43F. LC-MS(ESI) m/z: 208 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 3.89 (s, 2H),7.41-7.43 (m, 1H), 7.49 (s, 1H), 7.62 (d, J=8.8 Hz, 1H), 7.87 (d, J=1.6Hz, 1H).

To a solution of Compound 43F (2 g, 9.6 mmol) in methanol (10 mL) wasadded concentrated HCl (10 mL). The resulting mixture was stirred atreflux for 48 h. The reaction mixture was cooled to room temperature,extracted with dichloromethane (50 mL×2), washed with brine (50 mL),dried over anhydrous sodium sulfate, concentrated, and purified withflash column chromatography on silica gel (ethyl acetate in petroleumether, 10%, v/v) to furnish Compound 43G. LC-MS (ESI) m/z: 241 [M+H]⁺;¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 3.70 (s, 3H), 3.83 (s, 2H), 7.34-7.37(m, 2H), 7.65 (d, J=8.8 Hz, 1H), 7.82 (d, J=1.6 Hz, 1H).

To a solution of LiAlH₄ (221 mg, 5.8 mmol) in THF (20 mL) under nitrogenat −60° C. was added dropwise a solution of Compound 43G (1.4 g, 5.8mmol) in THF (5 mL). It was stirred under nitrogen at −60° C. for 1 h.The reaction mixture was diluted with ethyl acetate (50 mL) and addedNa₂SO₄.10H₂O. The mixture was filtered, concentrated, and purified withflash column chromatography on silica gel (ethyl acetate in petroleumether, 20%, v/v) to furnish Compound 43H. LC-MS (ESI) m/z: 213 [M+H]⁺;¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 2.33 (t, J=6.4 Hz, 1H), 3.09 (t, J=6.8Hz, 2H), 3.95 (t, J=6.8 Hz, 2H), 7.21 (s, 1H), 7.34-7.36 (m, 1H), 7.66(d, J=8.4 Hz, 1H), 7.83 (d, J=2.0 Hz, 1H).

A mixture of Compound 43H (1.2 g, 5.6 mmol), 2-oxoacetic acid hydrate(571 mg, 6.2 mmol) in CF₃COOH (5 mL) was stirred at reflux for 24 h. Themixture was evaporated to remove CF₃COOH. The mixture was diluted withethyl acetate (100 mL), washed with sat. sodium bicarbonate (50 mL×3)and brine (50 mL), dried over anhydrous sodium sulfate, concentrated,and purified with reverse phase chromatography using eluent(acetonitrile in NH₄OH and water, from 10% to 100% v/v) to furnishCompound 431. LC-MS (ESI) m/z: 269 [M+H]⁺.

A mixture of Compound 431 (80 mg, 0.30 mmol), Intermediate A (93 mg,0.30 mmol), and HATU (170 mg, 0.45 mmol) in DMF (5 mL) was stirred atroom temperature for 12 h. The mixture was treated with water (50 mL),extracted with dichloromethane (20 mL×2), washed with water (20 mL×3)and brine (50 mL), dried over anhydrous sodium sulfate, concentrated,and purified with prep-HPLC to furnish Compound 43. LC-MS (ESI) m/z: 561[M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ (ppm) 0.34-0.83 (m, 4H), 1.86-2.23(m, 4H), 2.82-3.26 (m, 5H), 3.48-3.67 (m, 4H), 3.83-4.07 (m, 2H),4.46-4.55 (m, 2H), 5.16-5.27 (m, 1H), 6.63-7.18 (m, 1H), 7.31-7.48 (m,3H), 7.65-7.91 (m, 3H).

Example 44

Compound 44 was synthesized by employing the procedure described forCompound 8 using Compound 33M and Intermediate F in lieu of Compound 8Fand Intermediate D. LC-MS (ESI) m/z: 526 [M+H]⁺; H-NMR (CD₃OD, 400 MHz):δ (ppm) 0.63-0.77 (m, 4H), 2.02-2.05 (m, 2H), 2.16-2.21 (m, 2H),3.33-3.35 (m, 2H), 3.51-3.55 (m, 1H), 3.66-3.81 (m, 4H), 4.68-4.71 (m,1H), 4.94 (m, 1H), 5.34 (m, 2H), 7.0-7.03 (m, 2H), 7.35-7.38 (m, 3H),7.54 (s, 1H), 7.78 (d, J=8.4 Hz, 1H).

Example 45

A suspension of Compound 45A (5.00 g, 26.70 mol),(bromomethyl)cyclohexane (7.10 g, 40.10 mmol), and K₂CO₃ (7.36 g, 53.34mmol) in DMF (20 mL) was stirred at 80° C. for 16 hours. The mixture wascooled down to room temperature, diluted with ethyl acetate (300 mL),and filtered. The filtrate was washed with water (200 mL×4) and brine(200 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated to give a crude product, which was purified with flashcolumn chromatography on silica gel (ethyl acetate in petroleum ether,from 0% to 8% v/v) to afford Compound 45B. LC-MS (ESI) m/z:non-ionizable compound under routine conditions used; ¹H-NMR (DMSO-d₆,400 MHz): δ (ppm) 0.95-1.28 (m, 5H), 1.63-1.79 (m, 6H), 2.29 (s, 3H),3.74 (d, J=6.4 Hz, 2H), 6.69-6.72 (m 1H), 6.95 (d, J=2.8 Hz, 1H), 7.41(d, J=8.8 Hz, 1H).

Compounds 45C, 45D, 45E, 45F, and 45G were synthesized by employing theprocedure described for Compounds 12B, 1D, 1E, 1F, and 1G usingCompounds 45B, 45C, 45D, 45E, and 45F in lieu of Compounds 12A, 1C, 1D,1E, and 1F.

Compounds 45C. LC-MS (ESI) m/z: 305 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ(ppm) 1.05-1.28 (m, 5H), 1.40 (t, J=7.2 Hz, 3H), 1.69-1.87 (m 6H), 2.61(s, 3H), 3.81 (d, J=2.0 Hz, 2H), 4.38-4.44 (m, 2H), 6.75-6.78 (m, 2H),7.66 (d, J=8.4 Hz, 1H).

Compounds 45D. LC-MS (ESI) m/z: 383 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ(ppm) 1.18-1.32 (m, 5H), 1.41 (t, J=7.2 Hz, 3H), 1.70-1.87 (m 6H), 3.85(d, J=6.4 Hz, 2H), 4.40-4.46 (m, 2H), 4.92 (s, 2H), 6.86-6.89 (m, 1H),7.05 (s, 1H), 7.72 (d, J=8.4 Hz, 1H).

Compounds 45E. LC-MS (ESI) m/z: 466 [M+H]; ¹H-NMR (CDCl₃, 400 MHz): δ(ppm) 1.01-1.32 (m, 5H), 1.39 (t, J=7.2 Hz, 3H), 1.69-1.88 (m, 6H), 3.91(d, J=5.6 Hz, 2H), 4.38-4.44 (m, 2H), 5.67 (s, 2H), 6.88-6.91 (m, 1H),7.58 (d, J=2.0 Hz, 1H), 7.74-7.77 (m, 3H), 7.84-7.88 (m, 2H).

Compounds 45F. LC-MS (ESI) m/z: 318 [M+H]; ¹H-NMR (CDCl₃, 400 MHz): δ(ppm) 1.87-1.25 (m, 5H), 1.43 (t, J=7.2 Hz, 3H), 1.70-1.87 (m, 6H), 3.80(d, J=6.4 Hz, 2H), 4.41-4.46 (m, 2H), 4.99 (s, 2H), 6.64 (d, J=2.0 Hz,1H), 6.89-6.91 (m, 1H), 7.86 (d, J=8.8 Hz, 1H).

Compounds 45G. LC-MS (ESI) m/z: 290 [M+H]⁺.

Compound 45 was synthesized by employing the procedure described forCompound 8 using Compound 45G and Intermediate A in lieu of Compound 8Fand Intermediate D. LC-MS (ESI) m/z: 582 [M+H]⁺; ¹H-NMR (CD₃OD, 400MHz): δ (ppm) 0.67-0.82 (m, 4H), 1.06-1.36 (m, 5H), 1.71-2.04 (m, 6H),3.14-3.21 (m, 4H), 3.17-3.31 (m, 2H), 3.49-3.55 (m, 1H), 3.66-3.85 (m,6H), 4.66-4.70 (m, 1H), 4.92-5.03 (m, 3H), 6.79-6.82 (m, 2H), 7.16 (d,J=8.8 Hz, 1H), 7.34 (s, 2H), 7.46 (s, 1H).

Example 46

Compound 46 was synthesized by employing the procedure described forCompound 8 using Compound 34L in lieu of Compound 8F. LC-MS (ESI) m/z:508 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ (ppm) 0.72-0.80 (m, 4H),2.05-2.23 (m, 4H), 3.21-3.31 (m, 2H), 3.56-3.59 (m, 1H), 3.69-3.86 (m,4H), 4.25 (s, 3H), 4.73 (d, J=10.8 Hz, 1H), 4.97 (s, 1H), 5.62 (q,J=13.6 Hz, 2H), 6.94 (d, J=8.4 Hz, 1H), 7.22-7.24 (m, 2H), 7.34 (t,J=6.4 Hz, 1H), 7.65 (d, J=8.8 Hz, 1H), 8.04 (s, 1H).

Example 47

Compound 47 was synthesized by employing the procedure described forCompound 8 using Compound 37P in lieu of Compound 8F. LC-MS (ESI) m/z:544 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ (ppm) 0.70-0.78 (m, 4H),2.06-2.22 (m, 4H), 3.22-3.32 (m, 2H), 3.57-3.58 (m, 1H), 3.68-3.84 (m,4H), 4.68-4.73 (m, 1H), 4.95 (s, 1H), 5.17-5.24 (m, 2H), 7.20-7.23 (m,2H), 7.31-7.37 (m, 2H), 7.46 (s, 1H), 7.70 (d, J=8.8 Hz, 1H).

Biological Examples

The following describes ways in which the compounds described hereinwere tested to measure in vitro activity in enzymatic and cell-basedassays. A person of ordinary skill in the art would know that variationsin the assay conditions could be used to determine the activity of thecompounds.

Assay 1: GCS Enzymatic Assay

This assay was modified based on the study by Larsen et al. (J. LipidRes. 2011, 53, 282). Madin-Darby canine kidney (MDCK) cell lysate wasprepared using M-PER Mammalian Protein Extraction Reagent (ThermalScientific) in the presence of a protease inhibitor cocktail (Roche).Protein concentration was determined using BCA assay kit (Pierce). Sixtymicrograms of MDCK cell lysate was incubated with various concentrationsof a compound described herein from 0.001 μM-10 μM, respectively, or asindicated in Table 2, in 100 mM Tris buffer (pH 7.5) containing 10 mMMgCl₂, 1 mM dithiothreitol, 1 mM EGTA, 2 mM NAD, 100 μM UDP-glucose, 10μM C6-NBD-Ceramide (Matreya LLC, Pleasant Gap, Pa.), 35 μMdioleoylphosphatidylcholine and 5 μM sulfatide (Sigma) in a finalreaction volume of 100 μL at 37° C. for 1 hour. 0.1% DMSO was used asmock treatment or control. The reaction was terminated by adding 100 μLacetonitrile solution and subjected to LC/MS analysis.

The quantitative analysis of NBD-Ceramide and glucosylceramide wasperformed on a Shimadzu ultra-fast liquid chromatography (Shimadzu,Japan) coupled with API 4000 triple quadrupole mass spectrometer(Applied Biosystems, Concord, Ontario, Canada). Sample separation wasconducted on a Waters Xbridge™ BEH130 C18, 100 mm×4.6 mm i.d, 3.5 m(Milford, Mass., USA). The mobile phase consisted of water andacetonitrile supplemented with 0.1% formic acid (v/v). The flow rate was1.0 mL/min. The initial mobile phase was 20% acetonitrile and was rampedin a linear fashion to 50% acetonitrile in 0.4 min. From 0.4 to 1.5 min,the gradient was ramped to 98% acetonitrile, and then was held at 100%until 8.0 min. Acetonitrile was reset to 20% in 1.5 min, and maintaineduntil 10.0 min. The total run time was 10.0 min. The MS/MS detection wasperformed in ESI positive mode. The mass transition of NBD-Ceramide wasm/z 576.36→558.40 under the collision energy of 15 V, and the masstransition of glucosylceramide was m/z 738.35→558.40 under 21V collisionenergy. The cell lysate was diluted with equal volume of acetonitrile.Aliquots of 50 μL diluted samples were added to 1.5 mL tubes, and 100 μLof acetonitrile containing internal standard (100 ng/mL tolbutamide)were added for protein precipitation. The mixture were vortexed and thencentrifuged at 13000 rpm for 10 min. 70 μL of supernatant were mixedwith 140 μL of H₂O and the final solution were injected for LC/MS/MSanalysis and IC₅₀'s and/or percent inhibitions calculated.

Assay 2: K562 Cell-Based Assay

This assay was modified based on the study by Gupta et al. (J. LipidRes. 2010, 51, 866). K562 cells were seeded into 12-well plates at 3×10⁵cells/well/mL in RPMI-1640 medium with 5% FBS and incubated at 37° C.for 24 h. One μL of a compound described herein at desired concentration(10 mM, 1 mM, 0.1 mM, 0.01 mM, 0.001 mM and 0.0001 mM in DMSO) or DMSOwas added into the corresponding well and mixed. Cells were incubated at37° C. for 4 h. Then 100 μL of RPMI-1640 medium containing 110 μM ofNBD-Ceramide, 11% BSA, 5% FBS, and corresponding concentration of acompound described herein was added into each well and mixed. Cells wereincubated for additional 0.5 h at 37° C., followed by washing the cellswith ice-cold PBS (pH 7.4) twice with centrifugation and resuspendedwith 50 μL cold PBS+1% Triton X-100. The cell lysate was sonicated for15 min before adding equal volume of methanol for LCMS analysis. A smallaliquot of cell lysate was used to determine protein concentration byBCA assay kit. The HPLC equipment and methods used in Assay 1 were usedin this assay as well and IC₅₀'s were calculated.

Assay 3: NCI/ADR-Res Cell-Based Assay

NCI/ADR-RES cells are seeded into 12-well plates (4×10⁵ cells/well) inRPMI-1640 medium with 10% FBS and incubated at 37° C. for 24 h. Beforetreatment with a compound described herein, cell culture media areremoved and replaced with 1 mL per well RPMI-1640 medium containing 5%FBS and a compound as described herein at desired concentrations (10 μM,1 μM, 0.1 μM, 0.01 μM, 0.001 μM, and 0.0001 μM), respectively, or 0.1%DMSO only. Cells are cultured for 4 hours at 37° C. followed byreplacing the media with RPMI-1640 containing 1% BSA and 10 μM ofC6-NBD-Ceramide in the present of a compound described herein, andincubated for additional 0.5 hour at 37° C. Cells are then washed twicewith ice-cold PBS (pH 7.4), scraped with 50 μL cold PBS+1% TritionX-100. The cell lysate is sonicated for 15 min before adding equalvolume of methanol for LCMS analysis. A small aliquot of cell lysate isused to determine protein concentration by BCA assay kit. The HPLCequipment and methods used in Assay 1 are used in this assay as well andIC₅₀'s are calculated.

Using the above assays, the following compounds were tested.

TABLE 2 Assay 1 Assay 2 (Enzyme Assay; (Cellular Assay; MDCK lysates)K562 cells) Example No. IC₅₀ IC₅₀ 1 A A 2 A A 3 A A 4 B A 5 B A 6 B A 7A A 8 A A 9 A A 10 B A 11 B A 12 B B 13 B ND 14 A A 15 C ND 16 C ND 17 AA 18 B A 19 B A 20 A A 21 B A 22 A A 23 C ND 24 B B 25 A A 26 A A 27 A B28 A A 29 A A 30 A B 31 B B 32 A A 33 A B 34 A B 36 A B 37 A A 38 B A 39B A 40 B ND 41 C ND 42 C ND 43 C ND 44 B A 45 A B 46 A A 47 A A

In Table 2, biological data is provided as follows:

IC₅₀ values:

A: <1 nM-10 nM;

B: >10-100 nM;

C: >100-1000 nM;

ND: not determined.

Sandhoff Disease Mouse Model

The murine model of Sandhoff disease is a knock out (KO) of the HEXBgene, which codes for beta-hexosaminidase in mice, as it does in humans.This KO mouse displays a phenotype closely resembling that seen inhumans, although at a more advanced age, compared to humans. At ˜3months of age, the animals develop tremor and increased limb tone, whichis worse in the hind legs. These manifestations become progressivelymore severe until 4-5 months of age, when the animals become moribundand rapidly lose weight. The motor phenotype has been quantified byactivity monitor, bar-crossing, and inverted screen tests (Jayakumar Met al Blood 2001, 97, 327-329; Cachon-Gonzalez et al PNAS 2006, 103(27),1037-10378). Histologically, the mouse neurons appear to be distended bylysosomal storage material, and signs of neuroinflammation are present.Biochemically, levels of beta-hexosaminidase are absent, andaccumulations of gangliosides GM2, GA2, as well as sialic acid, can bedemonstrated (Cachon-Gonzalez et al 2006; Arthur et al Neurochemn Res2013, DOI 10.1007/s11064-013-0992-5).

To evaluate the potential efficacy of different compounds describedherein in Sandhoff disease, homozygous male mice are mated withheterozygous females. All pups (approximately 50% KO and 50% het) in alitter are treated by daily IP or SC injection with the same test (orcontrol) article for 14 days, beginning at 3 days old. The chosen routeof administration is determined based on pharmacokinetic/pharmacodynamicproperties of the compound to be tested. At the end of the dosingperiod, pups are deeply anesthetized using isoflurane through nose cones(4% for induction and 1.5% for maintenance), blood is collected bycardiac puncture method, then the mice are euthanized. Brains and liversare collected and snap frozen. These tissues are used for analysis ofexperimental endpoints (GM2 and sialic acid in brain, GA2 and sialicacid in liver). An additional tissue sample (tail tip or toe) iscollected and snap frozen, then sent for genotyping.

If tested compounds are found which have a marked effect on theexperimental endpoints, an additional experiment is performed looking ateffects on activity, inverted screen, and bar crossing tests, as well asaverage survival time, compared to vehicle-treated mice.

Polycystic Kidney Disease Mouse Model

To jck mice is administered a compound described herein ad libitum infood (standard chow) from 26-64 days of age. Control jck mice are fed acontrol diet from 26-64 days of age. At 63 days of age, the animals aretransferred to metabolic cages for 24 hour urine collection. At 64 daysof age, animals are sacrificed, weighed, and blood is collected by heartpuncture for serum isolation. Kidneys are isolated, bisected, andweighed and half of each kidney is fixed in 4% paraformaldehyde in PBSovernight for paraffin embedding and hematoxylin and eosin staining.Kidney weight to body weight ratio is used to determine activity of thecompound. Cyst volume is measured by quantitating the percentage ofcystic area in histological sections of kidneys from the treated andcontrol animals and multiplied by the kidney/body weight ratio. Kidneyfunction is assessed by measuring blood urea nitrogen (BUN) levels inserum samples derived from animals at sacrifice. BUN levels are elevatedin untreated controls while the treated animals demonstrated asignificant reduction of BUN levels.

Other objects, features and advantages of the compounds, methods andcompositions described herein will become apparent from the followingdescription. It should be understood, however, that the description andthe specific examples, while indicating specific embodiments, are givenby way of illustration only, since various changes and modificationswithin the spirit and scope of the present description will becomeapparent from this detailed description.

All publications including patents, patent applications and publishedpatent applications cited herein are hereby incorporated by referencefor all purposes.

1.-35. (canceled)
 36. A method of treating a disease or disorder in asubject in need thereof, wherein the disease or disorder is selectedfrom the group consisting of a glycolipid storage disease, a diseaseassociated with glycolipid accumulation, a disease that causes renalhypertrophy or hyperplasia, a disease that causes hyperglycemia orhyperinsulemia, a cancer in which glycolipid synthesis is abnormal, aninfectious disease caused by organisms which use cell surfaceglycolipids as receptors or in which synthesis of glucosylceramide isessential or important, atherosclerosis, polycystic kidney disease,renal hypertrophy, diabetes mellitus, breast cancer, renaladenocarcinoma, brain cancer, neuroblastoma, lung cancer, intestinalcancer, pancreatic cancer, prostate cancer, a neuronal disorder, aneuronal injury, an inflammatory disease or disorder, obesity, andParkinson's disease; the method comprising administering to the subjectan effective amount of a compound of Formula I:

wherein R¹ is H; or R¹ and R² together form —OCH₂CH₂O—; R² is C₃₋₆cycloalkyloxy or 3-6 membered heterocycloalkyloxy; R³ is H or halogen;R⁴ is H or C₁₋₄ alkyl; R⁵ and R^(5A) are each independently H or C₁₋₄alkyl; X is N or O, and when X is N, the dashed line is a bond to form adouble bond, and when X is O, the dashed line is not a bond to form asingle bond; Y is C(R⁶)₂ or O; with the proviso that X and Y are notboth O; R⁶ at each occurrence is independently H or C₁₋₄ alkyl; Ring Ais phenylene, naphthylene, or 5-10 membered heteroarylene; R⁷ at eachoccurrence is independently halogen, C₁₋₆, alkyl, C₁₋₆ alkoxy, C₃₋₆cycloalkyloxy, (C₃₋₆ cycloalkyl)C₁₋₆ alkoxy, phenyl, or 5-6 memberedheteroaryl, wherein the phenyl and heteroaryl are each optionallysubstituted with 1, 2, or 3 R⁸; p is 0, 1, or 2; R⁸ at each occurrenceis independently halogen, cyano, amino, C₁₋₆ alkylamino, C₁₋₆dialkylamino, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, aminocarbonyl,C₁₋₆ alkylaminocarbonyl, or C₁₋₆ dialkylaminocarbonyl; Ring B is a 4-6membered heterocycloalkyl ring; R⁹ at each occurrence is independentlyhalogen, OR¹⁰, or N(R¹⁰)₂; R¹⁰ at each occurrence is independently H orC₁₋₄ alkyl; q is 0, 1, 2, 3, or 4; and optionally a single stereoisomeror mixture of stereoisomers thereof and additionally optionally apharmaceutically acceptable salt thereof.
 37. The method of claim 36,wherein R¹ is H; or R¹ and R² together form —OCH₂CH₂O—; R² is C₃₋₆cycloalkyloxy; R³ is H, Cl, or F; R⁴ is H or C₁₋₄ alkyl; R⁵ and R^(5A)are each independently H or C₁₋₄ alkyl; X is N or O, and when X is N,the dashed line is a bond to form a double bond, and when X is O, thedashed line is not a bond to form a single bond; Y is CH₂, CH(C₁₋₄alkyl), C(C₁₋₄ alkyl)₂, or O; with the proviso that X and Y are not bothO; Ring A is phenylene, naphthylene, benzothiophenylene, indazolylene,or quinolylene; R⁷ is Cl, F, C₁₋₆ alkyl, (C₃₋₆ cycloalkyl)C₁₋₆ alkoxy,phenyl, or thienyl, wherein the phenyl and thienyl are each optionallysubstituted with R⁸; R⁸ is Cl, F, or C₁₋₆ alkyl; and optionally a singlestereoisomer or mixture of stereoisomers thereof and additionallyoptionally a pharmaceutically acceptable salt thereof.
 38. The method ofclaim 36, wherein R¹ is H; or R¹ and R² together form —OCH₂CH₂O—; R² isC₃₋₆ cycloalkyloxy or 3-6 membered heterocycloalkyloxy; R³ is H orhalogen; R⁴ is H or C₁₋₄ alkyl; R⁵ and R^(5A) are each independently Hor C₁₋₄ alkyl; X is N or O, and when X is N, the dashed line is a bondto form a double bond, and when X is O, the dashed line is not a bond toform a single bond; Y is C(R⁶)₂ or O; with the proviso that X and Y arenot both O; R⁶ at each occurrence is independently H or C₁₋₄ alkyl; RingA is phenylene, naphthylene, or 5-10 membered heteroarylene; R⁷ at eachoccurrence is independently halogen, C₁₋₆ alkyl, phenyl, or 5-6 memberedheteroaryl, wherein the phenyl and heteroaryl are each optionallysubstituted with 1, 2, or 3 R⁸; p is 0, 1, or 2; R⁸ at each occurrenceis independently halogen, cyano, amino, C₁₋₆ alkylamino, C₁₋₆dialkylamino, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, aminocarbonyl,C₁₋₆ alkylaminocarbonyl, or C₁₋₆ dialkylaminocarbonyl; Ring B is a 4-6membered heterocycloalkyl ring; R⁹ at each occurrence is independentlyhalogen, OR¹⁰, or N(R¹⁰)₂; R¹⁰ at each occurrence is independently H orC₁₋₄ alkyl; q is 0, 1, 2, 3, or 4; and optionally a single stereoisomeror mixture of stereoisomers thereof and additionally optionally apharmaceutically acceptable salt thereof.
 39. The method of claim 38,wherein

is selected from the group consisting of

wherein the asterix indicates the point of attachment to the rest of themolecule.
 40. The method of claim 38, wherein Ring A is bicyclic. 41.The method of claim 38, wherein Ring A is phenylene, naphthylene,benzothiophenylene, indazolylene, or quinolylene.
 42. The method ofclaim 38, wherein Ring A is phenylene and R⁷ is phenyl or thienyl, eachsubstituted with halogen.
 43. The method of claim 42, wherein R⁷ isphenyl substituted with Cl or F, or R⁷ is thienyl substituted with Cl.44. The method of claim 38, wherein the compound of Formula I isaccording to Formula I(a):

optionally as a single stereoisomer or mixture of stereoisomers thereofand additionally optionally as a pharmaceutically acceptable saltthereof.
 45. The method of claim 38, wherein the compound of Formula Iis according to Formula I(b):

optionally as a single stereoisomer or mixture of stereoisomers thereofand additionally optionally as a pharmaceutically acceptable saltthereof.
 46. The method of claim 38, wherein the compound of Formula Iis according to any one of Formulae II to XII:

optionally as a single stereoisomer or mixture of stereoisomers thereofand additionally optionally as a pharmaceutically acceptable saltthereof.
 47. The method of claim 38, wherein p is 0 or
 1. 48. The methodof claim 47, wherein q is
 0. 49. The method of claim 36, where thecompound of Formula I is according to Formula XIII:

wherein R¹ is H; or R¹ and R² together form —OCH₂CH₂O—; R² is C₃₋₆cycloalkyloxy; R³ is H, Cl, or F; R⁴ is H or C₁₋₄ alkyl; R⁵ and R^(5A)are each independently H or C₁₋₄ alkyl; X is N or O, and when X is N,the dashed line is a bond to form a double bond, and when X is O, thedashed line is not a bond to form a single bond; Y is CH₂, CH(C₁₋₄alkyl), C(C₁₋₄ alkyl)₂, or O; with the proviso that X and Y are not bothO; Ring A is phenylene, naphthylene, benzothiophenylene, indazolylene,or quinolylene; R⁷ is Cl, F, C₁₋₆ alkyl, phenyl, or thienyl, where thephenyl and thienyl are each optionally substituted with R⁸; R⁸ is Cl, F,or C₁₋₆ alkyl; n is 1 or 2; and wherein the compound is optionally asingle stereoisomer or mixture of stereoisomers thereof and additionallyoptionally a pharmaceutically acceptable salt thereof.
 50. The method ofclaim 49, wherein the Ring A is phenylene, naphthylene orbenzothiophenylene.
 51. The method of claim 36, wherein the compound ofFormula I is selected from Table 1; optionally as a single stereoisomeror mixture of stereoisomers thereof and additionally optionally as apharmaceutically acceptable salt thereof.
 52. A method of treating adisease or disorder in a subject in need thereof, wherein the disease ordisorder is selected from the group consisting of a glycolipid storagedisease, a disease associated with glycolipid accumulation, a diseasethat causes renal hypertrophy or hyperplasia, a disease that causeshyperglycemia or hyperinsulemia, a cancer in which glycolipid synthesisis abnormal, an infectious disease caused by organisms which use cellsurface glycolipids as receptors or in which synthesis ofglucosylceramide is essential or important, atherosclerosis, polycystickidney disease, renal hypertrophy, diabetes mellitus, breast cancer,renal adenocarcinoma, brain cancer, neuroblastoma, lung cancer,intestinal cancer, pancreatic cancer, prostate cancer, a neuronaldisorder, a neuronal injury, an inflammatory disease or disorder,obesity, and Parkinson's disease; the method comprising administering tothe subject a pharmaceutical composition comprising i) an effectiveamount of a compound of Formula I:

wherein R¹ is II; or R¹ and R² together form —OCH₂CH₂O—; R² is C₃₋₆cycloalkyloxy or 3-6 membered heterocycloalkyloxy; R³ is H or halogen;R⁴ is H or C₁₋₄ alkyl; R⁵ and R^(5A) are each independently H or C₁₋₄alkyl; X is N or O, and when X is N, the dashed line is a bond to form adouble bond, and when X is O, the dashed line is not a bond to form asingle bond; Y is C(R⁶)₂ or O; with the proviso that X and Y are notboth O; R⁶ at each occurrence is independently H or C₁₋₄ alkyl; Ring Ais phenylene, naphthylene, or 5-10 membered heteroarylene; R⁷ at eachoccurrence is independently halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₆cycloalkyloxy, (C₃₋₆ cycloalkyl)C₁₋₆ alkoxy, phenyl, or 5-6 memberedheteroaryl, wherein the phenyl and heteroaryl are each optionallysubstituted with 1, 2, or 3 R⁸; p is 0, 1, or 2; R⁸ at each occurrenceis independently halogen, cyano, amino, C₁₋₆ alkylamino, C₁₋₆dialkylamino, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, aminocarbonyl,C₁₋₆ alkylaminocarbonyl, or C₁₋₆ dialkylaminocarbonyl; Ring B is a 4-6membered heterocycloalkyl ring; R⁹ at each occurrence is independentlyhalogen, OR¹⁰, or N(R¹⁰)₂; R¹⁰ at each occurrence is independently H orC₁₋₄ alkyl; q is 0, 1, 2, 3, or 4; and optionally as a singlestereoisomer or mixture of stereoisomers thereof and additionallyoptionally as a pharmaceutically acceptable salt thereof, and ii) apharmaceutically acceptable excipient.
 53. The method of claim 52,wherein the compound of Formula I is selected from Table 1; optionallyas a single stereoisomer or mixture of stereoisomers thereof andadditionally optionally as a pharmaceutically acceptable salt thereof.54. A method of treating a disease or disorder in a subject in needthereof, wherein the disease or disorder is selected from the groupconsisting of a glycolipid storage disease, a disease associated withglycolipid accumulation, a disease that causes renal hypertrophy orhyperplasia, a disease that causes hyperglycemia or hyperinsulemia, acancer in which glycolipid synthesis is abnormal, an infectious diseasecaused by organisms which use cell surface glycolipids as receptors orin which synthesis of glucosylceramide is essential or important,atherosclerosis, polycystic kidney disease, renal hypertrophy, diabetesmellitus, breast cancer, renal adenocarcinoma, brain cancer,neuroblastoma, lung cancer, intestinal cancer, pancreatic cancer,prostate cancer, a neuronal disorder, a neuronal injury, an inflammatorydisease or disorder, obesity, and Parkinson's disease; the methodcomprising administering to the subject an effective amount of acompound selected from Table 1; optionally as a single stereoisomer ormixture of stereoisomers thereof and additionally optionally as apharmaceutically acceptable salt thereof.